Mono- or polyenic carboxylic acid derivatives

ABSTRACT

To provide novel compounds relating to retinoid which can substitute for retinoic acid used for preventing and treating several diseases and having antagonism against retinoid. Heterocyclic compounds represented by the general formula (1-I) or physiologically acceptable salts thereof: 
     
         Z--(CR.sup.3 ═CR.sup.2).sub.n --COOR.sup.1--           (1-I) 
    
     Compounds represented by the general formula (2-I) or physiologically acceptable salts thereof: ##STR1## The compounds according to the present invention exhibit extremely high ability to bind RARs and are effective for treating various kind of diseases such as abnormality in cornification and rheumatoid arthritis.

This is a divisional of application Ser. No. 08/836,428, filed May 6,1997, now U.S. Pat. No. 5,977,125 which is a 371 of PCT/JP95/02231 filedOct. 31, 1995.

INDUSTRIAL FIELD OF APPLICATION

The first embodiment of the present invention relates to mono- orpolyenic carboxylic acid derivatives or physiologically acceptable saltsthereof or drugs containing the mono- or polyenic carboxylic acidderivatives or the physiologically acceptable salts thereof.

The second embodiment of the present invention relates to heterocycliccompounds. More particularly, it relates to novel heterocyclic compoundswhich are extremely effective in the prevention and treatment ofdiseases.

BACKGROUND OF THE INVENTION AND PRIOR ART

Retinoic acid (vitamin A acid, abbreviation: RA) is an essentialsubstance to the growth and life support of humans and other mammals. Ithas been known that retinoic acid acts as a morphogenesis factor inontogenesis and functions variously in the differentiation andproliferation of adults. For example, it has been known that the acidparticipates in the cornification, formation of hairs, functions ofsebaceous glands, and so on with respect to the epidermis, in themetabolism of bones and cartilages with respect to the connectivetissues, in the regulation of immune functions with respect to theimmune system, in the differentiation of nerve cells with respect to thenervous system, in the differentiation and proliferation of blood cellswith respect to the hemic system, and in the secretion of thyroidhormones, parathyroid hormones and so on and the regulation of thefunctions thereof in target organs, thus taking part in the mineralmetabolism and the basal metabolism. These various physiological actionsof retinoic acid are exhibited by directly controlling gene expressionthrough retinoid receptor (RARs, RXRs) family present in cell nuclei.With respect to retinoic acid, there are not only deficiencies but alsoexcesses thereof such as abnormality in cornification, depilation,metabolic disorder of bones and cartilages, and so on. Further, theabnormality of retinoid receptors has recently been found in acutepromyelocytic leukemia, head and neck squamous cell carcinoma, lungcancer and so on, and the participation of retinoic acid in thesideration and evolution thereof has been reported.

In order to elucidate detailed mechanisms of these various actions ofretinoids and to find the possibility for clinical application thereof,it has great significance to develop compounds antagonistic againstretinoids. Although TD-550 and TD-560 (Cell Biol. Rev., 25, 209(1991))and Ro41-5253 (Proc. Natl. Acad. Sci., U.S.A., 89, 7129 (1992)) havealready been known as compounds antagonistic against retinoids, they arethought to be poor in both the ability to bind RARs and antagonismagainst retinoids.

Meanwhile, RARs and RXRs are known as retionid receptors, which aremembers of steroid/thyroid receptor superfamily present in cell nuclei.Known receptors belonging to this superfamily include estrogen receptors(ER), thyroid hormone receptors (TR), vitamin D₃ receptors (D₃ R) andsteroid hormone receptors. With respect to RXRs, there are α-, β- andγ-subtypes, and the ligand thereof has recently been identified with9-cis RA. Further, it has been found that RXRs have the physiologicalproperty of forming heterodimers together with RXRs, TR, D₃ R or otherreceptors. Thus, it is being elucidated that RXRs act synergisticallywith their respective inherent ligands to take great part in theexpression of the functions of retinoic acid, vitamin D₃ or thyroidhormones through such heterodimers. In order to elucidate detailedmechanisms of these various actions of RXRs and to find the possibilityfor clinical application thereof, it has great significance to developcompounds binding to RXRs.

In view of the above actual circumstances, the inventors of the presentinvention have intensively studied to find that mono- or polyeniccarboxylic acid derivatives which will be described below exhibitagonism for RXRs and are useful as drugs. As the prior art, althoughJP-A-2-76862 and EP 0568898 disclose monoenic carboxylic acidderivatives and polyenic carboxylic acid derivatives these derivativesare different from the compounds of the present invention in bothchemical structure and drug effect.

Further, the inventors of the present invention have found thatheterocyclic compounds described below exhibit extremely high ability tobind RARs and antagonism against retinoids, thus accomplishing thepresent invention.

For example, JP-A-2-240058 discloses heterocyclic compounds whichexhibit such a function of agonist and are improved in the adversereaction due to retinoid excess. However, these compounds are differentfrom the compounds of the present invention in both chemical structureand drug effect.

DISCLOSURE OF THE INVENTION

The first embodiment of the present invention relates to mono- orpolyenic carboxylic acid derivatives represented by the formula (1-I) orphysiologically acceptable salts thereof:

    Z--(CR.sup.3 ═CR.sup.2).sub.n --COOR.sup.1--           (1-I)

[wherein R¹ is hydrogen or a carboxyl-protecting group; R² and R³ areeach independently hydrogen atom, halogen, linear lower alkyl, branchedlower alkyl, linear lower alkoxy, branched lower alkoxy or aryl; n is aninteger of 1 to 3; nR² 's or nR³ 's may be the same or different fromone another; and

Z is a group represented by the general formula (1-II), (1-III) or(1-IV): ##STR2## {wherein A, B and D are each carbon, nitrogen, sulfuror oxygen, with the carbon or nitrogen atom optionally bearing asubstituent; X¹ and Y¹ are each independently hydrogen, --NR⁴ R⁵, --CR⁶R⁷ R⁸, --OR⁹, --SR¹⁰, --S(→O)R¹¹ or --S(→O)₂ R¹² (wherein R⁴ and R⁵ areeach independently hydrogen, linear lower alkyl, branched lower alkyl orcycloalkyl; R⁶, R⁷ and R⁸ are each independently hydrogen, linear loweralkyl or branched lower alkyl; and R⁹, R¹⁰, R¹¹ and R¹² are eachindependently hydrogen, linear lower alkyl or branched lower alkyl, withthe proviso that when A or B is a carbon atom optionally bearing asubstituent, R⁴ or R⁵ together with the substituent of A or B may form aring), or alternatively X¹ and Y¹ together with the carbon atoms towhich they are bonded may form an optionally substituted, saturated orunsaturated ring which may contain oxygen, sulfur and/or nitrogen, andthe substituents on the saturated or unsaturated ring may be united toform a saturated or unsaturated ring which may contain oxygen, sulfurand/or nitrogen;

E is a carbon or nitrogen; F and G are each independently carbon,nitrogen, sulfur or oxygen, with the carbon or nitrogen atom optionallybearing a substituent; and X² and Y² are each independently hydrogen,--NR¹³ R¹⁴, --CR¹⁵ R¹⁶ R¹⁷, --OR¹⁸, --SR¹⁹, --S(→O)R²⁰ or --S(→O)₂ R²¹(wherein R¹³ and R¹⁴ are each independently hydrogen, linear loweralkyl, branched lower alkyl or cycloalkyl; R¹⁵, R¹⁶ and R¹⁷ are eachindependently hydrogen, linear lower alkyl or branched lower alkyl; andR¹⁸, R¹⁹, R²⁰ and R²¹ are each independently hydrogen, linear loweralkyl or branched lower alkyl), or alternatively X² and Y² may be unitedto form an optionally substituted, saturated or unsaturated ring whichmay contain oxygen, sulfur and/or nitrogen;

X³ and Y³ are each independently hydrogen, linear or branched loweralkyl, linear or branched lower alkoxy, cycloalkyl, aryl, heteroaryl,fluoroalkyl or halogeno; and

the symbol ...... represents a single bond or a double bond},

with the proviso that the cases wherein Z is ##STR3## (wherein F and Gare each as defined above) are excepted].

Preferable compounds of the present invention include mono- and polyeniccarboxylic acid derivatives and physiologically acceptable salts thereofas described above wherein Z is a group represented by the formula:##STR4## [wherein R^(a), R^(b), R^(c) and R^(d) are each independentlyhydrogen, linear or branched lower alkyl, linear or branched loweralkoxy, cycloalkyl, aryl, heteroaryl, fluoroalkyl or halogeno, oralternatively two of R^(a), R^(b), R^(c) and R^(d) may be united to forman optionally substituted, saturated or unsaturated ring which maycontain oxygen, sulfur and/or nitrogen; R^(a') and R^(b') are eachindependently hydrogen, linear or branched lower alkyl, linear orbranched lower alkoxy, cycloalkyl, aryl, heteroaryl or fluoroalkyl; m isa number of 0 to 3; m' is 0 or 1; and W is >NR^(e), >CR^(e) R^(f),>SR^(g), >S(→O), >S(→O)₂, O, N, CR^(e) or S (wherein R^(e), R^(f) andR^(g) are each independently hydrogen, linear or branched lower alkyl,linear or branched lower alkoxy, cycloalkyl, aryl, heteroaryl,fluoroalkyl or halogeno), with the proviso that both the W's in eachgroup may be the same or different from each other].

Further, preferable compounds of the present invention include mono- andpolyenic carboxylic acid derivatives and physiologically acceptablesalts thereof as described above, wherein Z is a group represented bythe formula: ##STR5##

The carboxyl-protecting group as defined for R¹ in the present inventionincludes lower alkyl groups such as methyl, ethyl and propyl.

The term "linear lower alkyl" used in the definition of R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R^(a), R^(b), R^(c), R^(d), R^(a'), R^(b'), R^(e), R^(f), R^(g), X³and Y³ refers to linear C₁ -C₆ alkyl, examples of which include methyl,ethyl, propyl, butyl, amyl and pentyl. Among them, methyl, ethyl andpropyl are preferable. The term "branched lower alkyl" used thereinrefers to isoproyl, isobutyl, sec-butyl, tert-butyl, amyl, isopentyl,neopentyl or the like, with isopropyl being preferable.

The term "linear lower alkoxy" used in the definition of R², R³, R^(a),R^(b), R^(c), R^(d), R^(a'), R^(b'), R^(e), R^(f), R^(g), X³ and Y³refers to linear C₁ -C₆ alkoxy, and examples thereof include methoxy,ethoxy, n-propoxy and n-butoxy. The term "branched lower alkoxy" usedtherein refers to isopropoxy, sec-butoxy or the like. The term"cycloalkyl" used in the definition of R⁴, R⁵, R¹³, R₁₄, R^(a), R^(b),R^(c), R^(d), R^(a'), R^(b'), R^(e), R^(f), R^(g), X³ and Y³ refers toC₃ -C₇ cycloalkyl, and examples thereof include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. Further, the term "halogeno"used in this description refers to fluoro, chloro or bromo.

The aryl as defined for R^(a), R^(b), R^(c), R^(d), R^(a'), R^(b'),R^(e), R^(f), R^(g), X³ and Y³ includes phenyl and so on; the heteroarylas defined therefor includes furyl and so on; and the fluoroalkyl asdefined therefor includes trifluoromethyl and so on.

Further, n is an integer of 1 to 3, with the cases wherein n is 3 beingmost desirable.

Preferable examples of the compounds represented by the formula (1-I)include the following compounds: ##STR6##

Further, the present invention relates also to mono- or polyeniccarboxylic acid derivatives represented by the general formula (1-V) orphysiologically acceptable salts thereof: ##STR7## [wherein R¹ ishydrogen or a protecting group; R², R³, R⁴, R⁵ and R⁶ are eachindependently hydrogen, halogeno, linear lower alkyl, branched loweralkyl, linear lower alkoxy or branched lower alkoxy; X and Y are eachindependently --NR⁷ R⁸, --CR⁹ R¹⁰ R¹¹, --OR¹², --SR¹³, --S(→O)R¹⁴, or--S(═O)₂ R¹⁵ (wherein R⁷ and R⁸ are each independently hydrogen, linearlower alkyl, branched lower alkyl or cycloalkyl; R⁹, R¹⁰ and R¹¹ areeach independently hydrogen, linear lower alkyl or branched lower alkyl;and R¹², R¹³, R¹⁴ and R¹⁵ are each independently hydrogen, linear loweralkyl or branched lower alkyl, or alternatively R⁷ or R⁸ together withR⁴ or R⁶ may form a ring), or alternatively X and Y together with thecarbon atoms to which they are bonded may form a ring which may containa double bond; A, B and D are each carbon, nitrogen, sulfur or oxygenand D may be nil; n is an integer of 1 to 3; and the broken line moietyrepresents a single bond or a double bond].

Preferable examples of the above compounds according to claim 1 includemono- and polyenic carboxylic acid derivatives represented by thegeneral formula (1-VI) and physiologically acceptable salts thereof:##STR8## [wherein X and Y are each independently --NR⁷ R⁸ or --CR⁹ R¹⁰R¹¹ (wherein R⁷ and R⁸ are each independently hydrogen, linear loweralkyl, branched lower alkyl or cycloalkyl; R⁹, R¹⁰ and R¹¹ are eachindependently hydrogen, linear lower alkyl or branched lower alkyl; andR¹², R¹³, R¹⁴ and R¹⁵ are each independently hydrogen, linear loweralkyl or branched lower alkyl, or alternatively R⁷ or R⁸ together withR⁴ or R⁶ may form a ring); Z is --(CR¹⁶ R¹⁷)₁ --, --(CR¹⁸)_(m) ═ or--(CR¹⁹ ═CR²⁰)_(p) -- (wherein R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are eachindependently hydrogen or lower alkyl; and l, m and p are each aninteger of 1 to 4); n is an integer of 1 to 3; and the broken linemoiety represents a single bond or a double bond].

The term "linear lower alkyl" used in the definition of R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ in the presentinvention refers to linear C₁ -C₆ alkyl, examples of which includemethyl, ethyl, propyl, butyl, amyl and pentyl. Among them, ethyl, ethyland propyl are preferable. The term "branched lower alkyl" used thereinrefers to isopropyl, isobutyl, sec-butyl, tert-butyl, amyl, isopentyl orneopentyl, with isopropyl being preferable. The term "lower alkyl" usedin the definition of R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ refers to methyl, ethyl,propyl, butyl, amyl, isopropyl, sec-butyl, tert-butyl or the like.

The term "linear lower alkoxy" used in the definition of R¹, R², R³, R⁴,R⁵ and R⁶ refers to linear C₁ -C₆ alkoxy, and examples thereof includemethoxy, ethoxy, n-propoxy and n-butoxy. The term "branched loweralkoxy" used therein refers to isopropoxy, sec-butoxy or the like. Theterm "cycloalkyl" used in the definition of R⁷ and R⁸ refers to C₃ -C₇cycloalkyl, and examples thereof include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. Further, the term "halogeno"used in this description refers to fluoro, chloro or bromo.

Specific examples of the above compounds wherein R⁷ or R⁸ together withR⁴ or R⁶ forms a ring include compounds as described above wherein X isNR⁷ R⁸, Y is CR⁹ R¹⁰ R¹¹, R⁷ and R⁸ form rings, R¹⁰ and R¹¹ arehydrogen, R⁸ is n-propyl or the like, and R⁷ and R⁴ are united to form aring, and such compounds are represented by, e.g., ##STR9##

When A, B and D are each carbon, the formula (1-V) can be represented by##STR10##

In the definition of Z in the general formula (1-VI), the cases whereinl is 1 or 2, m is 1 and p is 1 are preferable. Specific examples of thecompounds according this preferable embodiment include those representedby the formulae: ##STR11## Further, it is most desirable that n is 3.

Preferable examples of the compounds represented by the general formula(1-V) include the following compounds: ##STR12##

The second embodiment of the present invention relates to heterocycliccompounds represented by the following formula (2-I) or physiologicallyacceptable salts thereof: ##STR13## [wherein R¹ and R² are eachindependently hydrogen, lower alkyl, alkenylalkyl, alkynylalkyl,cycloalkyl, cycloalkylalkyl, lower alkoxyalkyl, aryl, heteroaryl orarylalkyl, or alternatively R¹ and R² may be united to form a 5- to7-membered cycloalkyl group which is substituted with a lower alkylgroup and may contain sulfur, oxygen, sulfinyl, sulfonyl or NR³ (whereinR³ is hydrogen or lower alkyl); the broken line moiety represents asingle bond or a double bond; A represents ##STR14## and

B represents ##STR15## (wherein R⁶ is hydrogen, lower alkyl,alkenylalkyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, loweralkoxyalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; R¹³ ishydrogen, lower alkyl or lower alkoxy; R⁷ is ##STR16## (wherein E isaryl, heteroaryl or ##STR17## (wherein R¹¹ and R¹² are each hydrogen orlower alkyl; and m is an integer of 1 to 3); and R⁸ is hydrogen,hydroxyl, lower alkoxy or --NR⁹ R¹⁰ (wherein R⁹ and R¹⁰ are eachindependently hydrogen, hydroxyl, lower alkyl, lower alkoxy,hydroxyalkyl, aryl, hydroxyaryl or heteroaryl, or alternatively R⁹ andR¹⁰ together with the nitrogen atom to which they are bonded may form aring which may contain nitrogen, oxygen or sulfur))].

Further, the present invention relates also to compounds represented bythe general formula (2-II) or (2-III) or physiologically acceptablesalts thereof: ##STR18## [wherein R¹ and R² are each independentlyhydrogen, lower alkyl, alkenylalkyl, alkynylalkyl, cycloalkyl,cycloalkylalkyl, lower alkoxyalkyl, aryl, heteroaryl or arylalkyl, oralternatively R¹ and R² may be united to form a 5- to 7-memberedcycloalkyl group which is substituted with a lower alkyl group and maycontain sulfur, oxygen, sulfinyl, sulfonyl or NR³ (wherein R³ ishydrogen or lower alkyl); the broken line moiety represents a singlebond or a double bond; and

B is a group represented by the formula: ##STR19## (wherein R⁶ ishydrogen, lower alkyl, alkenylalkyl, alkynylalkyl, cycloalkyl,cycloalkylalkyl, lower alkoxyalkyl, aryl, heteroaryl, arylalkyl orheteroarylalkyl; R¹³ is hydrogen, lower alkyl or lower alkoxy; and R⁷ is##STR20## (wherein E is aryl, heteroaryl or ##STR21## (wherein R¹¹ andR¹² are each hydrogen or lower alkyl; and m is an integer of 1 to 3);and R⁸ is hydrogen, hydroxyl, lower alkoxy or --NR⁹ R¹⁰ (wherein R⁹ andR¹⁰ are each independently hydrogen, hydroxyl, lower alkyl, loweralkoxy, hydroxyalkyl, aryl, hydroxyaryl or heteroaryl, or alternativelyR⁹ and R¹⁰ together with the nitrogen atom to which they are bonded mayform a ring which may contain nitrogen, oxygen or sulfur))].

The term "lower alkyl" used in the above definition for the compounds(2-I) to (2-III) according to the present invention refers to linear orbranched C₁ -C₆ alkyl, and examples thereof include methyl, ethyl,propyl, isopropyl, buty, isobutyl, sec-butyl, tert-butyl, amyl,isopentyl and neopentyl. Among them, methyl, ethyl, propyl and isopropylare preferbale. The term "lower alkoxy" used in the definition of R⁸,R⁹, R¹⁰ and R¹³ refers to methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy or the like. The term "cycloalkyl" used in the defintion of R⁶refers to C₃ -C₇ cycloalkyl, and examples thereof include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term"cycloalkylalkyl" used in the defintion of R⁶ refers to one derived fromthe above cycloalkyl, and representative examples thereof includecyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl andcyclohexylethyl. The term "bridged cyclic hydrocarbyl" refers toadamantyl, adamantylmethyl or the like. The term "aryl" used in thedefinition of R⁶, R⁹ and R¹⁰ refers to phenyl, naphthyl or the like,which may be substituted with lower alkyl such as methyl or ethyl,halogeno, lower alkoxy, hydroxyl or the like. The term "hydroxyaryl"used in the definition of R⁹ and R¹⁰ refers to a group comprising anaryl group such as phenyl or naphthyl and a hydroxyl group bondedthereto. The term "arylalkyl" used in the definition of R⁶ refers to onederived from the above aryl group. Preferable examples thereof includebenzyl and phenethyl. The above aryl group may be substituted with loweralkyl such as methyl or ethyl, halogeno, lower alkoxy, hydroxy or thelike.

The term "heteroaryl" used in the definition of R⁶ refers to a groupderived from a heterocycle, and examples thereof include pyridyl,thiazolyl, pyrimidyl, furyl and thienyl.

The term "heteroarylalkyl" used in the defintion of R⁶ refers to a groupderived from the above heteroaryl, and examples thereof includepyridylmethyl and pyridylethyl.

The term "lower alkoxyalkyl" used in the definition of R⁶ refers to agroup derived from the above lower alkoxy, examples thereof includingmethoxyethoxy, methoxypropoxy and ethoxyethoxy.

As defined above with respect to R⁹ and R¹⁰, R⁹ and R¹⁰ together withthe nitrogen atom to which they are bonded may form a ring which maycontain nitrogen, oxygen or sulfur. Examples of such a ring include thefollowing: ##STR22##

Compounds represented by the above general formula (2-I) orphysiologically acceptable salts thereof, wherein B represents asubstituted, 5- or 6-membered unsaturated heterocyclic structurecontaining one or two heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur, with such a heterocyclic structureincluding ##STR23## [wherein R¹³ is hydrogen, lower alkyl or loweralkoxy; and R⁷ is ##STR24## (wherein E is heteroaryl or ##STR25##(wherein R¹¹ and R¹² are each hydrogen or lower alkyl; and m is aninteger of 1 to 3); and R⁸ is --NR⁹ R¹⁰ (wherein R⁹ and R¹⁰ are eachindependently hydroxyaryl)].

Compounds represented by the above general formula (2-II) or (2-III) orphysiologically acceptable salts thereof, wherein R¹ and R² are eachindependently hydrogen, alkenylalkyl, alkylalkyl, cycloalkyl,cycloalkylalkyl, lower alkoxyalkyl, aryl, heteroaryl or arylalkyl, withthe cycloalkyl ring optionally contaning sulfur, oxygen, sulfinyl,sulfonyl or NR³ (wherein R³ is hydrogen or lower alkyl); and B is agroup represented by the formula: ##STR26## [wherein R¹³ is hydrogen,lower alkyl or lower alkoxy; and R⁷ is ##STR27## (wherein E isheteroaryl or ##STR28## (wherein R¹¹ and R¹² are each independentlyhydrogen or lower alkyl; and m is an integer of 1 to 3))].

In the present invention, the term "physiologically acceptable salts"refers to conventional nontoxic salts. Examples thereof includeinorganic acid salts such as hydrochloride, hydrobromide, sulfate andphosphate; organic acid salts such as acetate, maleate, oxalate,methanesulfonate, benzenesulfonate and toluenesulfonate; and amino acidsalts such as argininate, aspartate and glutamate. Further, some of thecarboxylic acid derivatives of the present invention take the form ofsalts with metals such as Na, K, Ca or Mg, and such salts are alsoincluded among the physiologically acceptable salts according to thepresent invention.

Preparation processes for preparing the compound according to the firstembodiment of the present invention will now be described. ##STR29## (inthe above reaction scheme, R^(d) is as defined above; R', R" and R'" areeach alkyl; J is hahogeno; L is H or halogeno; and R'M is anorganometallic reagent)

Preparation process 1

(i) An N-alkylate represented by the general formula (2) is prepared byreacting the compound (1) with an alkyl halide in the presence of abase. Better results can be attained when potassium carbonate, sodiumhydride or the like is used as the base. N,N-Dimethylformamide ortetrahydrofuran can be used as the solvent for this reaction. Thereaction temperature may range from 0° C. to the boiling point of thesolvent, preferably from 0° C. to 80° C.

(ii) An aldehyde represented by the general formula (3) is prepared fromthe N-alkylate (2) by the Vilsmeir process or the like.

(iii) An alcohol represented by the general formula (4) is prepared byreacting the aldehyde (3) with an organometallic reagent such as aGrignard reagent, organolithium reagent, organolithium-copper complex orthe like. Ethers such as diethyl ether or tetrahydrofuran can be used asthe solvent for this reaction. The reaction temperature may range from-78° C. to the boiling point of the solvent, preferably from -78° C. to20° C.

(iv) A ketone represented by the general formula (5) is prepared byoxidizing the alcohol (4) with a suitable oxidizing agent. The use ofactivated manganese dioxide, PCC, PDC, Swern oxidizing agent or the likeas the oxidizing agent gives good results. A solvent which is notoxidized with the oxidizing agent can be used for this reaction, such asolvent including dichloromethane and acetone. The reaction temperaturemay range from -78° C. to the boiling point of the solvent, preferablyfrom -78° C. to 20° C.

(v) An acrylic acid derivative represented by the general formula (6) isprepared by subjecting the ketone (5) to the Wittig-Horner reaction orthe Horner-Emmons reaction in the presence of a base. Better results canbe attained; when sodium hydride, sodium alkoxide, n-butyllithium,potassium t-butoxide or lithium bistrimethylsilylamide is used as thebase. The solvent usable in this reaction includesN,N-dimethylformamide, n-hexane, tetrahydrofuran and diethyl ether. Thereaction temperature may range from -78° C. to the boiling point of thesolvent, preferably -78° C. to 20° C.

(vi) An allyl alcohol represented by the general formula (7) is preparedby reducing the acrylic acid derivative (6) with a suitable reducingagent. Better results can be attained, when diisobutylaluminum hydrideor lithium borohydride is used as the reducing agent. Tetrahydrofuran,dichloromethane or the like can be used as the solvent for thisreaction. The reaction temperature may range from -78° C. to the boilingpoint of the solvent, preferably from -78° C. to 20° C.

(vii) An aldehyde represented by the general formula (8) is prepared byoxidizing the allyl alcohol (7) in a similar manner to that employed inthe step (iv).

(viii) A trienic carboxylic acid ester represented by the generalformula (9) is prepared by subjecting the aldehyde (8) to theWittig-Horner reaction or the Horner-Emmons reaction in a similar mannerto that employed in the step (v).

(ix) A trienic carboxylic acid derivative represented by the generalformula (10) is prepared by hydrolyzing the ester (9) in the presence ofa base. Better results can be attained, when an aqueous solution ofsodium hydroxide, potassium hydroxide or lithium hydroxide is used asthe base. Alcohols such as methanol, ethanol and so on can be used asthe solvent for this reaction. The reaction temperature may range from0° C. to the boiling point of the solvent, preferably from 20° C. to theboiling point of the solvent. ##STR30## (wherein R and R' are each asdefined above)

A dienic carboxylic acid ester represented by the general formula (11)is prepared by subjecting the aldehyde (8) to the Wittig-Horner reactionor the Horner-Emmons reaction in the presence of a base. Then, theobtained ester is converted into an aldehyde represented by the generalformula (12) by conventional reduction and oxidation. This aldehyde isfurther subjected to the Witting-Horner reaction or the Horner-Emmonsreaction in a similar manner to that described above to give a trieniccarboxylic acid ester represented by the general formula (13). Thisester is hydrolyzed by a conventional process into a trienic carboxylicacid represented by the general formula (14). ##STR31## (wherein R andR' are each as defined above)

An acrylic acid derivative represented by the general formula (15) isprepared by subjecting the aldehyde (3) to the Wittig-Horner reaction orthe Horner-Emmons reaction in the presence of a base. Then, the acidderivative is reduced and oxidized by conventional processes to give analdehyde represented by the general formula (16). This aldehyde issubjected to the Wittig-Horner reaction or the Horner-Emmons reaction ina similar manner to that described above to give a trienic carboxylicacid ester represented by the general formula (17). A trienic carboxylicacid represented by the general formula (18) is obtained by hydrolyzingthis ester in a conventional manner.

Representative processes for preparing the compounds according to thesecond embodiment of the present invention will now be described.##STR32## (in the reaction scheme, A, R⁶, R⁷ and broken line are each asdefined above; and X is halogen)

A diketone represented by the general formula (1) is prepared byreacting the ketone (2) with an acid chloride (3) in the presence of abase. Better results can be attained when lithium diisopropylamide,lithium bistrimethylsilylamide or the like is used as the base. Thesolvent usable for this reaction includes ethers such as diethyl ether,tetrahydrofuran and dimethoxyethane. The reaction temperature may rangefrom -78° C. to the boiling point of the solvent, preferably -78° C. to20° C.

A pyrazole represented by the general formula (4) is prepared byreacting the diketone (1) with hydrazine hydrate, while a pyrazolerepresented by the general formula (6) is prepared by reacting thediketone (1) with a mono-substituted hydrazine (5) and removingundesirable isomers from the obtained product by crystallization orcolumn chromatography.

Although this reaction can proceed without using any catalyst, it may beaccelerated by the addition of an acid useful also as a dehydratingagent, with such an acid including hydrochloric acid, sulfuric acid,acetic acid and polyphosphoric acid.

The solvent for the reaction may, in principle, be any one which isunreactive with hydrazine. Examples of such a solvent include alcoholssuch as methanol, ethanol and isopropanol; aromatic hydrocarbons such asbenzene, toluene and xylene; aprotic solvents such as dimethylformamideand dimethyl sulfoxide; and chlorinated hydrocarbons such asdichloromethane, chloroform and 1,2-dichloroethane. The reactiontemperature may range from 0° C. to the boiling point of the solvent,preferably from room temperature to the boiling point of the solvent.Alternatively, a compound represented by the general formula (6) can beprepared by reacting the compound (4) with a halide represented by thegeneral formula (7) in the presence of a base and removingsimultaneously formed undesirable isomers from the obtained product bycrystallization or column chromatography. Examples of the base usable inthis reaction include alkali metal compounds such as potassiumcarbonate, sodium hydride and potassium hydride; and alkali metalalkoxides such as sodium methoxide, sodium ethoxide and potassiumt-butoxide. The solvent usable for the reaction includesdimethylformamide, tetrahydrofuran and 1,2-dimethoxyethane. The reactiontemperature may range from 0° C. to the boiling point of the solvent.##STR33## (in the above reaction scheme, R¹, R², R⁶, R⁷, A and n areeach as defined above)

A compound represented by the general formula (8) is prepared byreacting a ketone represented by the general formula (2) with analdehyde represented by the general formula (9) in the presence of acatalytic amount of a base to form an alcohol (10), and dehydrating thisalcohol in the presence of an acid. The base to be used in thepreparation of the alcohol (10) is preferably alkali hydroxide such assodium hydroxide or potassium hydroxide. The solvent to be used thereinincludes methanol, ethanol, propanol, tetrahydrofuran anddimethylformamide. The reaction temperature may range from 0° C. to theboiling point of the solvent, preferably from 20° C. to 40° C.

The acid to be used in the above dehydration includes hydrochloric acid,sulfuric acid, p-toluene-sulfonic acid, trifluoroacetic acid, oxalicacid and phosphoric acid. The solvent to be used therein includes etherssuch as diethyl ether, tetrahydrofuran, 1,4-dioxane and1,2-dimethoxyethane; and aromatic hydrocarbons such as benzene, tolueneand xylene. The reaction temperature may range from 0° C. to the boilingpoint of the solvent. Some of the compounds (8) can be prepared directlyfrom the compounds (2) without dehydration.

Then, the compound (8) can be converted into a compound (11) by reactingthe compound (8) with a catalytic amount of a base in a solventcomprising nitromethane (and, if necessary, tetrahydrofuran, methanol,ethanol or the like, when the compound is difficultly soluble). The baseto be used in this reaction includes N-benzyltrimethylammoniumhydroxide, triethylamine and diisopropylethylamine. The reaction isconducted at a temperature ranging from 0° C. to the boiling point ofthe solvent, preferably from 0° C. to room temperature.

A ketal represented by the general formula (12) is prepared byconverting the compound (11) into a γ-ketoaldehyde through the Nefreaction (Chem. Rev., 55, 137 (1955)) and converting this ketoaldehydeinto a ketal. The conversion into a ketal can be attained by adding amineral acid such as sulfuric acid or hydrochloric acid to methanol andadding the λ-ketoaldehyde to the obtained mixture. The reactiontemperature may range from -78° C. to the boiling point of the solvent,preferably from -40° C. to room temperature.

A pyrrole (13) is prepared by reacting the dimethyl ketal (12) with aprimary amine represented by the general formula R⁶ --NH₂. The solventto be used in this reaction may be any one inert to the reaction.Preferable examples of such a solvent include aromatic hydrocarbons suchas benzene, toluene and xylene; ethers such as tetrahydrofuran and1,2-dimethoxyethane; and alcohols such as methanol and ethanol. Theabove reaction can proceed in such a solvent with which an acid iscoexistent. The acid to be used is preferably one useful also as adehydrating agent, and examples of such an acid include hydrochloricacid, sulfuric acid, glacial acetic acid and polyphosphoric acid.

The dimethyl ketal (12) can be converted also into a furan (14) byreating the with an acid. Sulfuric acid, polyphosphoric acid or the likeis used as the acid, and the reaction is conducted at 0 to 100° C.Further, a thiophene (15) can be obtained by reacting the ketal (12)with a sulfide such as phosphorus pentasulfide or hydrogen sulfide. Thesolvent to be used in this reaction includes aromatic hydrocarbons suchas benzene, toluene and xylene, and pyridine, while the reactiontemperature may range from 0° C. to the boiling point of the solvent,preferably from 50° C. to the boiling point of the solvent.

Pharmacological Experimental Examples will now be described toillustrate the effects of the compounds according to the secondembodiment of the present invention.

EXPERIMENTAL EXAMPLE

Receptor binding assay using human promyelocytic leukemia cell HL60

It is known that all-trans retinoic acid receptors (retinoic acidreceptor: RAR) are is present in the nuclei of HL60 cells (Clara Nerviet al., Proc. Natl. Acad. Sci. U.S.A. 86, 5854(1989)). Therefore, thespecific binding of all-trans retinoic acid for RAR was determined bythe use of the nuclear extract fraction of HL60, and each test compoundwas examined for the ability to bind RAR by determining the inhibitionagainst the specific binding.

The nuclear extract fraction was prepared as follows.

HL60 cells (5×10⁸) were suspended in 15 ml of solution A (sodiumphosphate (pH7.4): 5 mM, monothioglycerol: 10 mM, glycerol: 10% (v/v),phenylmethylsulfonyl fluoride (PMSF): 1 mM, aprotinin: 10 μg/ml, andleupeptin: 25 μg/ml). The obtained suspension was homogenized by the useof a homogenizer and centrifuged to remove the resulting supernatant.The sediment thus formed was suspended in 15 ml of solution B (Tris-HCl(pH8.5): 10 mM, monothioglycerol: 10 mM, glycerol: 10% (v/v), PMSF: 1mM, aprotinin: 10 μg/ml, leupeptin: 25 μg/ml, and KCl: 0.8 M). Theobtained suspension was allowed to stand at 4° C. for one hour, andsubjected to ultracentrifugation (100,000× g, 4° C., 1 hr). The obtainedsupernatant was stored as the nuclear extract fraction in a frozen stateat -80° C. until the use (METHODS IN ENZYMOLOGY, 189, 248).

The receptor binding assay was conducted as follows.

180 μl of the above fraction and 10 μl of a dilution of all-transretinoic acid or a test compound were added to each well of a 96-wellplate made of polypropylene, followed by the addition of 10 μl of 10 nM³H-all-trans retinoic acid. The resulting plate was allowed to stand at4° C. for 16 hours. A solution containing 3% of charcoal and 0.3% ofdextran was added to the resulting reaction mixture. The mixture thusobtained was centrifuged to remove free ³ H-all-trans retinoic acid. Theradioactivity of the resulting supernatant was determined by the use ofa scintillation counter. The specific binding of ³ H-all-trans retinoicacid for RAR was determined by assuming the radioactivity found when 200times as much all-trans retinoic acid was added to be the non-specificbinding and subtracting it from the radioactivity determined above. Thecompounds which will be described below inhibited the binding of ³H-all-trans retinoic acid dependently on the concentration. The 50%inhibitory concentration of each test compound was calculated and theresults are given in Table 1.

Antagonism against all-trans retinoic acid in inducing thedifferentiation of HL60 cells

It is known that human promyelocytic leukemia cells HL60 differentiateinto granulocyte-like cells in the presence of all-trans retinoic acid(Breitman, T., Selonick, S., and Collins, S., Proc. Natl. Acad. Sci.U.S.A. 77, 2936(1980)). In general, cells allow specific differentiationantigens to be expressed on the cell surfaces when they have achieveddifferentiation. When HL60 cells differentiate into granulocyte-likecells, CD11b which is a granulocyte/monocyte discriminating antigen isexpressed on the cell surfaces (Fontana, J A., Reppuci, A., Durham, JP., and Mirand, D., Cancer Res. 46, 2469-2473 (1986)). The antagonism ofa test compound against the differentiation into granulocyte-like cellsinduced by all-trans retinoic acid was studied by utilizing thisphenomenon.

HL60 cells were cultured and maintained in a medium prepared by adding10% of inactivated fetal bovine serum, 1 mM of sodiumpyridinecarboxylate, 50 μM of β-mercaptoethanol, 100 IU/ml of penicillinand 100 μg/ml of streptomycin to RPMI1640 (culture medium formulated byRosewell Park Memorial Institute).

An HL60 cell suspension (1×10⁵ cells/ml) was put in a 48-well plate inan amount of one ml per unit well, followed by the addition of all-transretinoic acid in a concentration of 10 mM and a retinoid antagonist invarious concentrations. The resulting mixtures were cultured in a 5% CO₂-air incubator for 5 days. After the completion of the culture, thecells in each well was recovered into a test tube, followed by theaddition of an FITC-labeled monoclonal antibody against CD11b (which isa specific antigen against glanulocytes and monocytes). The resultingcell suspension was fixed with 0.2% paraformaldehyde. The fixed cellsuspension thus obtained was examined for the content of CD11b-positivecells in the HL60 cell population of each well by flow cytometry(Miller, L J., Schwarting, R., and Springer, T A., J. Immunol. 137,2891-2900 (1986)). The compounds which will be described below loweredthe content of CD11b-positive cells induced by 10 nM all-trans retinoicacid dependently on the concentration. The 50% inhibitory concentrationof each test compound was calculated and the results are given in Table1.

                  TABLE 1                                                         ______________________________________                                                  Receptor-  Antagonism against all-trans                                binding assay retinoic acid in inducing                                       using HL60 the differentiation of HL60                                       Ex. No. IC.sub.50 (nM) IC.sub.50 (nM)                                       ______________________________________                                        4         20         74                                                         5 5.4 39                                                                      8 17 470                                                                      9 >50 880                                                                     13 12.5 29                                                                    14 13 130                                                                     TD-550* 50 2100**                                                             TD-650* >50 2600**                                                          ______________________________________                                         *Cell Biol. Rev., 25, 209(1991)                                               **antagonism against alltrans retinoic acid (3 nM)                       

It is apparent from the results of the above Experimental Examples thatthe compounds of the present invention have an extremely high ability tobind RARs and an antagonism against all-trans retinoic acid. Therefore,the compounds of the present invention can be expected to be efficaciousagainst the following diseases:

various cornification anomalies, psoriasis, acne, leukoplakia, andxeroderma pigmentosum;

various alopeciae such as alopecia areata, seborrheic alopecia andcachectic alopecia;

postmenopausal osteoporosis, senile osteoporosis, idiopathicosteoporosis, diabetic osteopenia, rheumatoid osteopenia, renalosteomalacia and ectopic hyperostosis;

rheumatoid arthritis, osteoarthritis, and shoulder periarthritis;

activation of immunofunction in immunodefficiencies, infectious diseasesin hypofunction or of fetus with cytomegalovirus, and opportunisticinfection;

hyperthyroidism;

squamous cell carcinoma, bladder cancer, lung cancer, esophagealcarcinoma, and head and neck cancer;

hyperkalemia; and

pulmonary fibrosis, hepatic fibrosis, and hepatic cirrhosis.

The compounds of the present invention may be orally administered aspreventive or therapeutic agents for these diseases in the form oftablet, powder, granule, capsule, syrup or the like, or may beparenterally administered in the form of suppository, injection,external preparation or drop.

Pharmaceutical preparations for oral or parenteral administrationaccording to the present invention can be formulated by the use ofconventional pharmaceutically acceptable carriers in a conventionalmanner.

Subcutaneous, intramuscular or intravenous injections or droppinginjections according to the present invention can be formulated byconventional processes of adding a pH regulator, buffer, stabilizer orsolubilizing agent to a base at need and, if necessary, freeze-dryingthe obtained mixture.

BRIEF DESCRIPTION OF DRAWING

FIG. 1 shows the activities of the compounds of the present invention ofaccelerating transcription through retinoid X receptor α (RXR α).

EXAMPLE

Examples 1 to 132 relate to the first embodiment of the presentinvention, and Examples 201 to 214 relate to the second embodimentthereof.

The compounds according to the first embodiment of the present inventionwill now be described in more detail, though the present invention isnot limited by them.

In the Examples, Me and Et represent methyl and ethyl, respectively.

Example 1 Synthesis of ethyl(E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenoate##STR34## Step 1 Synthesis of1-(1-methylethyl)-1,2,3,4-tetrahydroquinoline ##STR35##

13.8 g (0.1 mmol) of 1,2,3,4-tetrahydroquinoline was dissolved in 60 mlof N,N-dimethylformamide, followed by the addition of 21.1 g (0.124mmol) of isopropyl iodide and 20.6 g (0.208 mol) of potassium carbonate.The obtained mixture was stirred under heating at 60° C. for 5 hours.Water was added to the resulting reaction mixture, followed by theextraction with ethyl acetate. The organic phase was washed with asaturated aqueous solution of common salt, dried over anhydrousmagnesium sulfate, and concentrated in a vacuum. The obtained residuewas purified by silica gel column chromatography (3% ethylacetate/n-hexane) to give 13.1 g of the title compound as a colorlessoil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.20(d, J=6.8 Hz, 6H), 1.92(tt, J=6.0, 6.0Hz, 2H), 2.76(t, J=6.0 Hz, 2H), 3.18(t, J=6.0 Hz, 2H), 4.13(hept., J=6.8Hz, 1H), 6.57(dt, J=0.8, 7.2 Hz, 1H), 6.71(d, J=8.4 Hz, 1H), 6.97(dd,J=1.2, 7.6 Hz, 1H), 7.05-7.10(m, 1H).

Step 2

Synthesis of1-(1-methylethyl)-1,2,3,4-tetrahydroquinoline-6-carbaldehyde ##STR36##

18.6 g (0.12 mol) of phosphorus oxychloride was dropped into 29.2 g (0.4mol) of N,N-dimethylformamide under cooling with ice. The obtainedmixture was stirred at room temperature for 30 minutes and cooled againon an ice bath. 17.5 g (0.1 mol) of1-(1-methylethyl)-1,2,3,4-tetrahydroquinoline was gradually dropped intothe resulting mixture. The mixture thus obtained was stirred at roomtemperature for one hour and poured onto ice-water. The resultingmixture was neutralized with an aqueous solution of sodiumhydrogencarbonate and extracted with ethyl acetate. The organic phasewas dried over anhydrous magnesium sulfate and concentrated in a vacuum.The residue was purified by silica gel column chromatography (10% ethylacetate/n-hexane) to give 11.4 g of the title compound as areddish-brown oil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.23(d, J=6.5 Hz, 6H), 1.90(tt, J=6.0, 6.0Hz, 2H), 2.75(t, J=6.0 Hz, 2H), 3.27(t, J=6.0 Hz, 2H), 4.20(hept., J=6.5Hz, 1H), 6.69(d, J=9.0 Hz, 1H), 7.45(d, J=2.0 Hz, 1H), 7.55(dd, J=2.0,9.0 Hz, 1H).

Step 3

Synthesis of1-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]ethanol ##STR37##

4.9 ml (15 mmol) of a 3.0 M ethereal solution of methylmagnesium bromidewas diluted with 15 ml of ether. An ethereal solution of 2.0 g (10 mmol)of 1-(1-methylethyl)-1,2,3,4-tetrahydroquinoline-6-carbaldehyde wasdropped into the dilution prepared above at room temperature. Theobtained mixture was stirred at room temperature for one hour, followedby the addition of an aqueous solution of ammonium chloride. Theresulting mixture was extracted with thyl acetate. The organic phase waswashed with a saturated aqueous solution of common salt, dried overanhydrous magnesium sulfate and concentrated in a vacuum to give 2.1 gof the title compound as a brown oil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=6.5 Hz, 6H), 1.48(d, J=6.5 Hz, 3H),1.91(tt, J=6.0, 6.0 Hz, 2H), 2.75(t, J=6.0 Hz, 2H), 3.17(t, J=6.0 Hz,2H), 4.11(hept., J=6.5 Hz, 1H), 4.76(q, J=6.0 Hz, 1H), 6.67(d, J=9.0 Hz,1H), 6.99(d, J=2.0 Hz, 1H), 7.07(dd, J=2.0, 9.0 Hz, 1H).

Step 4

Synthesis of1-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]ethanone ##STR38##

2.1 g of 1-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]ethanolwas dissolved in 10 ml of acetone, followed by the addition of 10 g ofactivated manganese dioxide. The obtained mixture was stirred at roomtemperature for 16 hours and filtered though Celite to remove themanganese dioxide. The filtrate was concentrated in a vacuum and theobtained residue was purified by silica gel column chromatography (10%ethyl acetate/n-hexane) to give 1.3 g of the title compound as apale-yellow crystal.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.22(d, J=6.5 Hz, 6H), 1.89(.tt, J=6.0, 6.0Hz, 2H), 2.48(s, 3H), 2.75(t, J=6.0 Hz, 2H), 3.24(t, J=6.0 Hz, 2H),4.19(hept., J=6.5 Hz, 1H), 6.63(d, J=9.0 Hz, 1H), 7.59(dd, J=2.0 Hz,1H), 7.69(dd, J=2.0, 9.0 Hz, 1H).

Step 5

Synthesis of ethyl(E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenoate##STR39##

2.20 g (60%, 51 mol) of sodium hydride was suspended in 10 ml ofN,N-dimethylformamide, and 11.3 g (51 mmol) of ethyldiethylphosphonoacetate was dropped into the suspension under coolingwith ice. The obtained mixture was stirred at room temperature for onehour, followed by the addition of 5.5 g (25 mmol) of1-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]ethanone. Theobtained mixture was stirred at 60° C. for 48 hours, followed by theaddition of water. The mixture thus obtained was extracted with ethylacetate. The organic phase was washed with a saturated aqueous solutionof common salt, dried over anhydrous magnesium sulfate and concentratedin a vacuum. The residue was purified by silica gel columnchromatography (4% ethyl acetate/n-hexane) to give 4.0 g of the titlecompound as a colorless oil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.20(d, J=6.5 Hz, 6H), 1.31(t, J=6.5 Hz, 3H),1.90(tt, J=6.0, 6.0 Hz, 6.0 Hz, 2H), 2.55(d, J=1.0 Hz, 3H), 2.74(t,J=6.0 Hz, 2H), 3.20(t, J=6.0 Hz, 2H), 4.13(hept., J=6.5 Hz, 1H), 4.19(q,J=6.5 Hz, 2H), 6.09(q, J=1.0 Hz, 1H), 6.64(d, J=9.0 Hz, 1H), 7.18(d,J=2.0 Hz, 1H), 7.29(dd, J=2.0, 9.0 Hz, 1H).

Example 2 Synthesis of(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-3-methyl-octa-2,4,6-trienoicacid ##STR40## Step 1 Synthesis of(E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenol##STR41##

1.0 g of ethyl(E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenateprepared in Example 1 was dissolved in 20 ml of tetrahydrofuran. Theobtained solution was cooled to -70° C., followed by the gradualaddition of 7.0 ml (10.5 mmol) of a 1.5 M solution of diisobutylaluminumhydride in toluene. The obtained mixture was stirred for 2 hours,followed by the addition of an aqueous solution of ammonium chloride.The obtained mixture was extracted with ethyl acetate. The organic phasewas washed with a saturated aqueous solution of common salt, dried overanhydrous magnesium sulfate and concentrated in a vacuum to give 650 mgof the title compound as a colorless oil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.18(d, J=6.5 Hz, 6H), 1.90(tt, J=6.0, 6.0Hz, 2H), 2.04(s, 3H), 2.74(t, J=6.0 Hz, 2H), 3.17(t, J=6.0 Hz, 2H),4.11(hept., J=6.5 Hz, 1H), 4.18(bd, J=5.0 Hz, 1H), 4.33(d, J=6.5 Hz,2H), 5.89(t, J=6.5 Hz, 1H), 6.64(d, J=8.5 Hz, 1H), 7.06(d, J=2.0 Hz,1H), 7.14(dd, J=2.0, 8.5 Hz, 1H).

Step 2

(E)-3-[1-(1-Methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenal##STR42##

650 mg of(E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenal wasdissolved in 10 ml of acetone, followed by the addition of 3.5 g ofactivated manganese dioxide. The obtained mixture was stirred at roomtemperature for 16 hours and filtered through Celite to remove themanganese dioxide. The filtrate was concentrated in a vacuum, and theobtained residue was purified by silica gel column chromatography (10%ethyl acetate/hexane) to give 400 mg of the title compound as apale-yellow oil.

¹ H-NMR(⁴⁰⁰ MHz, CDCl₃) δ: 1.22(d, J=6.5 Hz, 6H), 1.91(tt, J=6.0, 6.0Hz, 2H), 2.50(s, 3H), 2.75(t, J=6.0 Hz, 3H), 3.23(t, J=6.0 Hz, 2H),4.16(hept., J=6.5 Hz, 1H), 6.41(d, J=8.0 Hz, 1H), 6.67(d, J=9.0 Hz, 1H),7.26(d, J=2.0 Hz, 1H), 7.38(dd, J=2.0, 9.0 Hz, 1H), 10.10(d, J=8.0 Hz,1H).

Step 3

Methyl(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-3-methyl-octa-2,4,6-trienoate##STR43##

56 mg (2.46 mmol) of metallic sodium was added to methanol to prepare amethanolic solution of sodium methoxide. This solution was concentratedin a vacuum and suspended in N,N-dimethylformamide, followed by theaddition of 560 mg (2.14 mmol) of triethyl 3-methyl-4-phosphonocrotonateunder cooling with ice. After 30 minutes, 400 mg (1.64 mmol) of(E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenal wasadded to the mixture obtained above. The mixture thus obtained wasstirred for one hour, followed by the addition of an aqueous solution ofammonium chloride. The obtained mixture was extracted with ethylacetate. The organic phase was dried over anhydrous magnesium sulfateand concentrated in a vacuum. The obtained residue was purified bysilica gel column chromatography (15% ethyl acetate/n-hexane) to give330 mg of the title compound as a reddish-brown oil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.20(d, J=6.8 Hz, 6H), 1.91(tt, J=6.0, 6.0Hz, 2H), 2.20(s, 3H), 2.38(d, J=0.8 Hz, 3H), 2.75(t, J=6.0 Hz, 2H),3.19(t, J=6.0 Hz, 2H), 3.72(s, 3H), 4.15(hept., J=6.8 Hz, 1H), 5.77(s,1H), 6.32(d, J=15.2 Hz, 1H), 6.53(d, J=11.2 Hz, 1H), 6.65(d, J=8.8 Hz,1H), 7.06(dd, J=11.2, 15.2 Hz, 1H), 7.15(d, J=2.4 Hz, 1H), 7.25(dd,J=2.4, 8.8 Hz, 1H).

Step 4

(E,E,E)-7-[1-(1-Methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-3-methyl-octa-2,4,6-trienoicacid ##STR44##

330 mg of methyl(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-3-methylocta-2,4,6-trienoatewas dissolved in 10 ml of ethanol, followed by the addition of 1.0 ml ofa 5N aqueous solution of sodium hydroxide. The obtained mixture washeated at 60° C. for one hour and adjusted to pH5 by adding 6Nhydrochloric acid under cooling with ice. The crystals thus precipitatedwere recovered by filtration and recrystallized from ethanol to give 100mg of the title compound as orange crystals.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=6.5 Hz, 6H), 1.91(tt, J=6.0, 6.0Hz, 2H), 2.21(s, 3H), 2.39(s, 3H), 2.75(t, J=6.0 Hz, 2H), 3.19(t, J=6.0Hz, 2H), 4.13(hept., J=6.5 Hz, 1H), 5.79(s, 1H), 6.35(d, J=15.0 Hz, 1H),6.55(d, J=11.0 Hz, 1H), 6.66(d, J=9.0 Hz, 1H), 7.10(dd, J=15.0, 11.0 Hz,1H), 7.16(d, J=2.0 Hz, 1H), 7.26(dd, J=9.0, 2.0 Hz, 1H).

Example 3 Synthesis of(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-octa-2,4,6-trienoicacid ##STR45## Step 1 Synthesis of ethyl(E,E)-5-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-hexa-2,4-dienoate##STR46##

The title compound was prepared by the use of(E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenal in asimilar manner to that described in Step 5 of Example 1.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=6.8 Hz, 6H), 1.31(t, J=7.2 Hz, 3H),1.87-1.94(m, 2H), 2.24(d, J=1.2 Hz, 3H), 2.75(t, J=6.0 Hz, 2H), 3.20(t,J=6.0 Hz, 2H), 4.15(hept., J=7.2 Hz, 1H), 4.22(q, J=7.2 Hz, 2H), 5.88(d,J=14.8 Hz, 1H), 6.54(dt, J=0.8, 12.0 Hz, 1H), 6.65(d, J=9.2 Hz, 1H),7.17(d, J=2.8 Hz, 1H), 7.27(dd, J=2.4, 8.8 Hz, 1H), 7.77(dd, J=12.0,15.2 Hz, 1H).

Step 2

Synthesis of(E,E)-5-[1-(1-methylethyl)-1,2,3,4-tetradrouinolin-6-yl]-hexa-2,4-dienal##STR47##

The title compound was prepared by the use of ethyl(E,E)-5-[1-(1-methyethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-hexa-2,4-dienoatein a similar manner to that described in Steps 1 and 2 of Example 2.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.21(d, J=6.4 Hz, 7H), 1.87-1.95(m, 2H),2.29(d, J=1.2 Hz, 3H), 2.76(t, J=6.0 Hz, 2H), 3.22(t, J=6.0 Hz, 2H),4.13(hept., J=7.2 Hz, 1H), 6.19(dd, J=8.0, 14.8 Hz, 1H), 6.66(d, J=8.8Hz, 1H), 6.71(bd, J=11.6 Hz, 1H), 7.22(d, J=2.4 Hz, 1H), 7.33(dd, J=2.4,8.8 Hz, 1H), 7.59(dd, J=12.0, 14.8 Hz, 1H), 9.60(d, J=8.0 Hz, 1H).

Step 3

Synthesis of ethyl(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-octa-2,4,6-trienoate##STR48##

The title compound was prepared in a similar manner to that described inStep 5 of Example 1.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=6.8 Hz, 6H), 1.30(t, J=7.2 Hz, 3H),1.91(tt, J=5.6, 6.4 Hz, 2H), 2.19(s, 3H), 2.75(t, J=6.4 Hz, 2H), 3.19(t,J=5.6 Hz, 2H), 4.13(hept., J=6.8 Hz, 1H), 4.21(q, J=7.2 Hz, 2H), 5.83(d,J=15.2 Hz, 1H), 6.36(dd, J=11.6, 14.4 Hz, 1H), 6.53(d, J=11.2 Hz, 1H),6.65(d, J=9.2 Hz, 1H), 6.86(dd, J=11.6, 14.4 Hz, 1H), 7.15(d, J=2.4 Hz,1H), 7.25(dd, J=2.4, 8.8 Hz, 1H), 7.42(dd, J=11.6, 14.8 Hz, 1H).

Step 4

Synthesis of(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-octa-2,4,6-trienoicacid ##STR49##

The title compound was prepared in a similar manner to that described inStep 4 of Example 2.

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.11(d, J=6.8 Hz, 6H), 1.74-1.83(m, 2H),2.10(s, 3H), 2.65(t, J=6.4 Hz, 2H), 3.12(t, J=5.6 Hz, 2H), 4.09(hept.,J=6.8 Hz, 1H), 5.79(d, J=15.2 Hz, 1H), 6.41(dd, J=11.6, 14.0 Hz, 1H),6.55(d, J=12.0 Hz, 1H), 6.64(d, J=9.2 Hz, 1H), 7.08(dd, J=12.0, 14.4 Hz,1H), 7.12(d, J=2.0 Hz, 1H), 7.20(dd, J=2.0, 9.2 Hz, 1H), 7.25(dd,J=11.6, 15.2 Hz, 1H).

Example 4 Synthesis of(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-3,6-dimethyl-hepta-2,4,6-trienoicacid ##STR50## Step 1 Synthesis of ethyl(E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-methyl-2-acrylate##STR51##

800 mg (60%, 20 mmol) of sodium hydride was suspended in 10 ml ofN,N-dimethylformamide. 4.8 g (20 mmol) of triethylphosphono-2-propionate was dropped into the suspension under coolingwith ice. The obtained mixture was stirred at room temperature for onehour, followed by the addition of 2.0 g of1-(1-methylethyl)-1,2,3,4-tetrahydroquinoline-6-carbaldehyde. Theobtained mixture was stirred at room temperature for one hour, followedby the addition of water. The mixture thus obtained was extracted withethyl acetate, and the organic phase was washed with a saturated aqueoussolution of common salt, dried over anhydrous magnesium sulfate, andconcentrated in a vacuum. The residue was purified by silica gel columnchromatography (10% ethyl acetate/n-hexane) to give 2.0 g of the titlecompound as a colorless oil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=6.8 Hz, 6H), 1.33(t, J=6.4 Hz, 3H),1.90(tt, J=6.0, 6.0 Hz, 2H), 2.15(s, 3H), 2.74(t, J=6.0 Hz, 2H), 3.20(t,J=6.0 Hz, 2H), 4.14(hept., J=6.8 Hz, 1H), 4.23(q, J=6.4 Hz, 2H),6.68(bd, J=8.8 Hz, 1H), 7.24(bd, J=8.8 Hz, 1H), 7.56(bs, 1H).

Step 2

Synthesis of3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-methyl-2-propenal##STR52##

The title compound was prepared in a similar manner to that described inSteps 1 and 2 of Example 2.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.22(d, J=6.8 Hz, 6H), 1.91(tt, J=6.0, 6.0Hz, 2H), 2.09(d, J=1.2 Hz, 3H), 2.76(t, J=6.4 Hz, 2H), 3.25(t, J=6.0 Hz,2H), 4.17(hept., J=6.8 Hz, 1H), 6.71(d, J=8.8 Hz, 1H), 7.06(s, 1H),7.22(d, J=2.4 Hz, 1H), 7.35(dd, J=2.4, 8.8 Hz, 1H), 9.44(s, 1H).

Step 3

Synthesis of methyl(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-3,6-dimethylhepta-2,4,6-trienoate##STR53##

The title compound was prepared in a similar manner to that described inStep 3 of Example 2.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=6.8 Hz, 6H), 1.91(tt, J=6.0, 6.0Hz, 2H), 2.08(s, 3H), 2.37(s, 3H), 2.74(t, J=6.0 Hz, 2H), 3.19(tt, J=6.0Hz, 2H), 3.19(tt, J=6.0 Hz, 2H), 3.71(s, 3H), 4.15(hept., J=6.8 Hz, 1H),5.80(s, 1H), 6.27(d, J=15.6 Hz, 1H), 6.55(s, 1H), 6.66(d, J=8.8 Hz, 1H),6.80(d, J=15.2 Hz, 1H), 7.00(d, J=1.2 Hz, 1H), 7.12(dd, J=1.2, 8.4 Hz,1H).

Step 4

Synthesis of(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-3,6-dimethylhepta-2,4,6-trienoicacid ##STR54##

The title compound was prepared in a similar manner to that described inStep 4 of Example 2.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.20(d, J=6.8 Hz, 6H), 1.91(tt, J=6.0 Hz,2H), 2.10(s, 3H), 2.39(s, 3H), 2.74(t, J=6.0 Hz, 2H), 3.20(t, J=6.0 Hz,2H), 4.14(hept., J=6.8 Hz, 1H), 5.83(s, 1H), 6.30(d, J=15.6 Hz, 1H),6.57(s, 1H), 6.67(d, J=8.8 Hz, 1H), 6.84(d, J=15.6 Hz, 1H), 7.01(d,J=1.2 Hz, 1H), 7.13(dd, J=1.6, 8.4 Hz, 1H).

Example 5 Synthesis of(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid ##STR55## Step 1 Synthesis of ethyl(E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-fluoro-2-butenoate##STR56##

450 mg (60%, 12 mmol) of sodium hydride was suspended in 10 ml ofN,N-dimethylformamide. 3.3.g (14 mmol) of ethyl2-fluoro-diethylphosphonoacetate was dropped into the suspension undercooling with ice. The obtained mixture was stirred under cooling withice for 30 minutes, followed by the addition of 2.0 g (9.2 mmol) of1-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl)ethanone. Theobtained mixture was stirred under cooling with ice for one hour,followed by the addition of an aqueous solution of ammonium chloride.The obtained mixture was extracted with ethyl acetate, and the organicphase was washed with a saturated aqueous solution of common salt, driedover anhydrous magnesium sulfate and concentrated in a vacuum. Theresidue was purified by silica gel column chromatography to give 2.3 gof the title compound as a colorless oil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.14(t, J=7.2 Hz, 3H), 1.18(d, J=6.8 Hz, 6H),1.89(tt, J=6.0, 6.0 Hz, 2H), 2.12(d, J=4.8 Hz, 3H), 2.71(t, J=6.0 Hz,2H), 3.17(t, J=6.0 Hz, 2H), 4.12(hept., J=6.8 Hz, 1H), 4.12(q, J=7.2 Hz,2H), 6.61(d, J=8.4 Hz, 1H), 6.81(d, J=2.0 Hz, 1H), 6.92(dd, J=2.4, 8.8Hz, 1H).

Step 2

Synthesis of(E)-3-[1-(1-methylethyl)-1,2,3,4-tetdroquinolin-6-yl]-2-fluoro-2-butenol##STR57##

The title compound was prepared in a similar manner to that described inStep 1 of Example 2.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.18(d, J=6.8 Hz, 6H), 1.90(tt, J=6.0 Hz,2H), 1.98(d, J=3.6 Hz, 3H), 2.72(t, J=6.0 Hz, 2H), 3.17(t, J=6.0 Hz,2H), 4.09(hept., J=6.8 Hz, 1H), 4.22(dd, J=6.0, 22.4 Hz, 2H), 6.63(d,J=8.4 Hz, 1H), 6.82(d, J=2.4 Hz, 1H), 6.91(dd, J=2.4, 8.4 Hz, 1H).

Step 3

Synthesis of(E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-fluoro-2-butenal##STR58##

The title compound was prepared in a similar manner to that described inStep 2 of Example 2.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.21(d, J=6.8 Hz, 6H), 1.91(tt, J=6.0, 6.0Hz, 2H), 2.25(d, J=3.6 Hz, 3H), 2.73(t, J=6.0 Hz, 2H), 3.22(t, J=6.0 Hz,2H), 4.12(hept., J=6.8 Hz, 1H), 6.66(d, J=8.8 Hz, 1H), 6.92(d, J=2.4 Hz,1H), 7.02(dd, J=2.4, 8.4 Hz, 1H), 9.35(d, J=19.6 Hz, 1H).

Step 4

Synthesis of methyl(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate##STR59##

The title compound was prepared in a similar manner to that described inStep 3 of Example 2.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.21(d, J=6.8 Hz, 6H), 1.92(tt, J=6.0, 6.0Hz, 2H), 2.12(d, J=3.6 Hz, 3H), 2.21(d, J=0.8 Hz, 3H), 2.74(t, J=6.0 Hz,2H), 3.20(t, J=6.0 Hz, 2H), 3.70(s, 3H), 4.13(hept., J=6.8 Hz, 1H),5.84(s, 1H), 6.50(d, J=15.6 Hz, 1H), 6.66(d, J=8.4 Hz, 1H), 6.68(dd,J=15.6, 26.4 Hz, 1H), 6.87(d, J=2.4 Hz, 1H), 6.95(dd, J=2.4, 8.4 Hz,1H).

Step 5

Synthesis of(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid ##STR60##

The title compound was prepared in a similar manner to that described inStep 4 of Example 2.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.21(d, J=6.4 Hz, 6H), 1.92(tt, J=6.0, 6.0Hz, 2H), 2.12(d, J=3.2 Hz, 3H), 2.21(s, 3H), 2.74(t, J=6.0 Hz, 2H),3.20((t, J=6.0 Hz, 2H), 5.86(s, 1H), 6.52(d, J=15.6 Hz, 1H), 6.66(d,J=8.4 Hz, 1H), 6.71(dd, J=15.6, 26.4 Hz, 1H), 6.87(d, J=2.0 Hz, 1H),6.95(dd, J=2.4, 8.8 Hz, 1H).

Example 6 Synthesis of(E,E,Z)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid ##STR61## Step 1 Synthesis of ethyl(Z)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-fluoro-2-butenoate##STR62##

The title compound was prepared in a similar manner to that described inStep 1 of Example 5 through separation and purification by silica gelcolumn chromatography.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.20(d, J=6.4 Hz, 6H), 1.37(t, J=7.2 Hz, 3H),1.91(tt, J=6.0, 6.0 Hz, 2H), 2.43(d, J=3.2 Hz, 3H), 2.73(t, J=6.0 Hz,2H), 3.20(t, J=6.0 Hz, 2H), 4.13(hept., J=6.4 Hz, 1H), 4.31(q, J=7.2 Hz,2H), 6.66(d, J=8.8 Hz, 1H), 7.13(d, J=2.0 Hz, 1H), 7.23(dd, J=2.0, 8.8Hz, 1H).

Step 2

Synthesis of(Z)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-fluoro-2-butenal##STR63##

The title compound was prepared in a similar manner to that described inSteps 1 and 2 of Example 2.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.21(d, J=6.8 Hz, 6H), 1.91(tt, J=6.0, 6.0Hz, 2H), 2.42(d, J=3.2 Hz, 3H), 2.75(t, J=6.0 Hz, 2H), 3.23(t, J=6.0 Hz,2H), 4.17(hept., J=6.8 Hz, 1H), 6.68(d, J=9.2 Hz, 1H), 7.32(d, J=3.2 Hz,1H), 7.44(dd, J=3.2, 9.2 Hz, 1H), 9.89(d, J=16.8 Hz, 1H).

Step 3

Methyl(E,E,Z)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoate##STR64##

The title compound was prepared in a similar manner to that described inStep 3 of Example 2.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=6.4 Hz, 6H), 1.92(tt, J=6.0, 6.0Hz, 2H), 2.13(d, J=2.8 Hz, 3H), 2.37(d, J=0.8 Hz, 3H), 2.74(t, J=6.0 Hz,2H), 3.19(t, J=6.0 Hz, 2H), 3.72(s, 3H), 4.14(hept., J=6.4 Hz, 1H),5.87(s, 1H), 6.56(d, J=15.2 Hz, 1H), 6.66(d, J=9.2 Hz, 1H), 6.83(dd,J=15.2, 26.4 Hz, 1H), 7.16(d, J=1.2 Hz, 1H), 7.26(dd, J=1.2, 9.2 Hz,1H).

Step 4

Synthesis of(E,E,Z)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid ##STR65##

The title compound was prepared in a similar manner to that described inStep 4 of Example 2.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=6.4 Hz, 6H), 1.92(tt, J=6.0, 6.0Hz, 2H), 2.13(d, J=2.8 Hz, 3H), 2.37(bs, 3H), 2.74(t, J=6.0 Hz, 2H),3.19(t, J=6.0 Hz, 2H), 4.12(hept., J=6.4 Hz, 1H), 5.84(bs, 1H), 6.58(bd,J=15.2 Hz, 1H), 6.66(d, J=8.4 Hz, 1H), 6.83(dd, J=15.2, 26.4 Hz, 1H),7.16(bs, 1H), 7.25-7.26(m, 1H).

The following compounds were prepared in a similar manner to thatdescribed above.

Example 7 Ethyl(E)-3-[1-(1-methylethyl)-4-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.13(t, J=7.2 Hz, 3H), 1.18(d, J=6.4 Hz, 3H),1.20(d, J=6.4 Hz, 3H), 1.24(d, J=6.8 Hz, 3H), 1.60-1.70(m, 1H),1.86-1.96(m, 1H), 2.13(d, J=4.8 Hz, 3H), 2.78-2.88(m, 1H), 3.14-3.23(m,2H), 4.05-4.18(m, 3H), 6.63(d, J=8.4 Hz, 1H), 6.89(d, J=2.4 Hz, 1H),6.93(dd, J=2.4, 8.8 Hz, 1H).

Example 8 Methyl(E,E,E)-7-[1-(1-methylethyl)-4-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.21(d, J=6.0 Hz, 3H), 1.22(d, J=6.0 Hz, 3H),1.26(d, J=7.2 Hz, 3H), 1.62-1.72(m, 1H), 1.89-1.97(m, 1H), 2.13(d, J=4.0Hz, 3H), 2.21(d, J=0.8 Hz, 3H), 2.81-2.90(m, 1H), 3.13-3.25(m, 2H),3.70(s, 3H), 4.14(hept., J=6.4 Hz, 1H), 5.84(s, 1H), 6.50(d, J=16.0 Hz,1H), 6.68(d, J=8.4 Hz, 1H), 6.69(dd, J=15.6, 26.0 Hz, 1H), 6.94(d, J=2.4Hz, 1H), 6.98(dd, J=2.4, 8.4 Hz, 1H).

Example 9(E,E,E)-7-[1-(1-Methylethyl)-4-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.21(d, J=5.6 Hz, 3H), 1.22(d, J=6.4 Hz, 3H),1.27(d, J=6.8 Hz, 3H), 1.62-1.71(m, 1H), 1.90-1.98(m, 1H), 2.14(d, J=3.6Hz, 3H), 2.22(s, 3H), 2.81-2.90(m, 1H), 3.17-3.23(m, 2H), 4.14(hept.,J=6.8 Hz, 1H), 5.87(bs, 1H), 6.53(d, J=15.6 Hz, 1H), 6.68(d, J=8.8 Hz,1H), 6.73(dd, J=16.0, 26.8 Hz, 1H), 6.95(d, J=2.4 Hz, 1H), 6.98(dd,J=2.4, 8.8 Hz, 1H).

Example 10 Ethyl(E)-3-[1-(1-methylethyl)-4-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.20(d, J=6.4 Hz, 3H), 1.21(d, J=6.8 Hz, 3H),1.27(d, J=6.8 Hz, 3H), 1.31(t, J=7.2 Hz, 3H), 1.63-1.71(m, 1H)1.87-1.95(m, 1H), 2.56(d, J=1.2 Hz, 3H), 2.81-2.91(m, 1H), 3.16-3.24(m,2H), 4.15(hept., J=6.4 Hz, 1H), 4.19(q, J=7.2 Hz, 2H), 6.10(d, J=0.8 Hz,1H), 6.66(d, J=9.6 Hz, 1H), 7.26-7.30(m, 2H).

Example 11 Methyl(E,E,E)-7-[1-(1-methylethyl)-4-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=6.4 Hz, 3H), 1.21(d, J=6.4 Hz, 3H),1.28(d, J=7.2 Hz, 3H), 1.61-1.72(m, 1H), 1.88-1.98(m, 1H), 2.21(d, J=0.8Hz, 3H), 2.38(d, J=0.8 Hz, 3H), 2.83-2.92(m, 1H), 3.18-3.22(m, 2H),3.71(s, 3H), 4.13(hept., J=6.4 Hz, 1H), 5.77(s, 1H), 6.33(d, J=14.8 Hz,1H), 6.53(bd, J=11.2 Hz, 1H), 6.67(d, J=8.4 Hz, 1H), 7.06(dd, J=11.2,14.8 Hz, 1H), 7.23-7.27(m, 2H).

Example 12(E,E,E)-7-[1-(1-Methylethyl)-4-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=7.2 Hz, 3H), 1.21(d, J=7.2 Hz, 3H),1.29(d, J=6.8 Hz, 3H), 1.62-1.72(m, 1H), 1.87-1.99(m, 1H), 2.22(bs, 3H),2.39(bs, 3H), 2.82-2.93(m, 1H), 3.13-3.25(m, 2H), 4.14(hept., J=7.2 Hz,1H), 5.79(s, 1H), 6.35(d, J=14.8 Hz, 1H), 6.55(d, J=11.2 Hz, 1H),6.67(d, J=8.4 Hz, 1H), 7.11(dd, J=11.2, 14.8 Hz, 1H), 7.21-7.28(m, 2H).

Example 13 Ethyl(E)-3-[1-(1-methylethyl)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.03(d, J=6.4 Hz, 3H), 1.14(t, J=7.2 Hz, 3H),1.16(d, J=6.4 Hz, 3H), 1.18(d, J=6.4 Hz, 3H), 1.90-2.02(m, 1H), 2.12(d,J=4.8 Hz, 3H), 2.39(dd, J=10.0, 15.2 Hz, 1H), 2.66-2.75(m, 2H),3.20(ddd, J=2.0, 4.0, 10.0 Hz, 1H), 4.09-4.15(m, 3H), 6.61(d, J=8.8 Hz,1H), 6.80(d, J=2.4 Hz, 1H), 6.92(dd, J=2.4, 8.8 Hz, 1H).

Example 14 Methyl(E,E,E)-7-[1-(1-methylethyl)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-6-flucro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.05(d, J=6.8 Hz, 3H), 1.19(d, J=6.4 Hz, 3H),1.21(d, J=6.8 Hz, 3H), 1.96-2.02(m, 1H), 2.11(d, J=4.0 Hz, 3H), 2.20(s,3H), 2.41(dd, J=10.4, 15.6 Hz, 1H), 2.69-2.78(m, 2H), 3.23(ddd, J=2.0,4.0, 10.0 Hz, 1H), 3.70(s, 3H), 4.12(hept., J=6.8 Hz, 1H), 5.84(s, 1H),6.49(d, J=15.6 Hz, 1H), 6.65(d, J=9.2 Hz, 1H), 6.67(dd, J=15.2, 26.8 Hz,1H), 6.85(d, J=2.0 Hz, 1H), 6.95(dd, J=2.0, 8.8 Hz, 1H).

Example 15(E,E,E)-7-[1-(1-Methylethyl)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.05(d, J=6.4 Hz, 3H), 1.19(d, J=6.8 Hz, 3H),1.21(d, J=6.4 Hz, 3H), 1.94-2.04(m, 1H), 2.12(d, J=3.6 Hz, 3H), 2.21(s,3H), 2.41(dd, J=10.8, 15.6 Hz, 1H), 2.69-2.76(m, 2H), 3.23(ddd, J=2.0,4.0, 10.0 Hz, 1H), 5.86(s, 1H), 6.52(d, J=15.6 Hz, 1H), 6.65(d, J=8.4Hz, 1H), 6.71(dd, J=15.2, 26.4 Hz, 1H), 6.86(d, J=2.0 Hz, 1H), 6.95(dd,J=2.0, 8.4 Hz, 1H).

Example 16 Ethyl(E)-3-[1-(1-methylethyl)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.04(d, J=6.4 Hz, 3H), 1.18(d, J=6.4 Hz, 3H),1.20(d, J=6.4 Hz, 3H), 1.31(t, J=7.2 Hz, 3H), 1.90-2.02(m, 1H), 2.41(dd,J=10.0, 15.6 Hz, 1H), 2.70-2.80(m, 2H), 3.22(ddd, J=2.0, 4.0, 10.0 Hz,1H), 4.14(hept., J=6.4 Hz, 1H), 4.18(q, J=7.2 Hz, 2H), 6.09(d, J=1.2 Hz,1H), 6.63(d, J=8.8 Hz, 1H), 7.18(d, J=2.4 Hz, 1H), 7.28(dd, J=2.4, 8.8Hz, 1H).

Example 17 Methyl(E,E,E)-7-[1-(1-methylethyl)-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.05(d, J=6.4 Hz, 3H), 1.17(d, J=6.4 Hz, 3H),1.20(d, J=6.8 Hz, 3H), 1.92-2.02(m, 1H), 2.20(d, J=0.8 Hz, 3H), 2.38(d,J=1.2 Hz, 3H), 2.42(dd, J=10.4, 15.6 Hz, 1H), 2.69-2.80(m, 2H),3.22(ddd, J=2.0, 4.0, 10.0 Hz, 1H), 3.71(s, 3H), 4.13(hept., J=6.4 Hz,1H), 5.77(s, 1H), 6.32(d, J=14.8 Hz, 1H), 6.53(d, J=11.2 Hz, 1H),6.64(d, J=9.2 Hz, 1H), 7.06(dd, J=11.2, 14.8 Hz, 1H), 7.14(d, J=2.0 Hz,1H), 7.25(dd, J=2.0, 8.8 Hz, 1H).

Example 18(E,E,E)-7-[1-(1-Methylethyl)-3-methyl-1,2,3,4-tatrahydroquinolin-6-yl]-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.05(d, J=6.4 Hz, 3H), 1.18(d, J=6.8 Hz, 3H),1.20(d, J=6.8 Hz, 3H), 1.90-2.03(m, 1H), 2.21(bs, 3H), 2.39(bs, 3H),2.42(dd, J=10.4, 15.6 Hz, 1H), 2.68-2.82(m, 2H), 3.18-3.26(m, 1H),4.14(hept., J=6.4 Hz, 1H), 5.79(bs, 1H), 6.34(d, J=15.2 Hz, 1H), 6.55(d,J=12.0 Hz, 1H), 6.65(d, J=9.2 Hz, 1H), 7.10(dd, J=11.2, 14.8 Hz, 1H),7.15(d, J=1.2 Hz, 1H), 7.24-7.28(m, 1H).

Example 19 Ethyl(E)-3-[1-(1-methylethyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.08(d, J=6.4 Hz, 3H), 1.12(t, J=7.2 Hz, 3H),1.19(d, J=6.8 Hz, 3H), 1.27(d, J=6.8 Hz, 3H), 1.65-1.75(m, 2H), 2.13(d,J=4.4 Hz, 3H), 2.63(dd, J=4.4, 16.8 Hz, 1H), 2.86(ddd, J=6.0, 13.6, 16.4Hz, 1H), 3.68-3.77(m, 1H), 4.06-4.15(m, 3H), 6.66(d, J=8.4 Hz, 1H),6.86(d, J=2.4 Hz, 1H), 6.92(dd, J=2 4, 8.4 Hz, 1H).

Example 20 Methyl(E,E,E)-7-[1-(1-methylethyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.12(d, J=6.4 Hz, 3H), 1.22(d, J=6.4 Hz, 3H),1.29(d, J=6.8 Hz, 3H), 1.64-1.80(m, 2H), 2.13(d, J=3.6 Hz, 3H), 2.22(s,3H), 2.61-2.69(m, 1H), 2.84-2.94(m, 1H), 3.70(s, 3H), 3.70-3.78(m, 1H),4.11(hept., J=6.4 Hz, 1H), 5.84(s, 1H), 6.50(d, J=15.6 Hz, 1H), 6.69(d,J=8.8 Hz, 1H), 6.70(dd, J=15.6, 26.4 Hz, 1H), 6.92(d, J=2.4 Hz, 1H),6.96(dd, J=2.4, 8.8 Hz, 1H).

Example 21(E,E,E)-7-[1-(1-Methylethyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.12(d, J=6.4 Hz, 3H), 1.22(d, J=6.4 Hz, 3H),1.29(d, J=6.8 Hz, 3H), 1.60-1.80(m, 2H), 2.13(d, J=4.0 Hz, 3H), 2.22(s,3H), 2.65(dd, J=4.4, 16.8 Hz, 1H), 2.89(ddd, J=6.0, 13.6, 16.4 Hz, 1H),3.70-3.80(m, 1H), 4.11(hept., J=6.4 Hz, 1H), 5.86(s, 1H), 6.53(d, J=16.8Hz, 1H), 6.70(d, J=8.4 Hz, 1H), 6.74(dd, J=16.0, 26.4 Hz, 1H), 6.92(d,J=2.0 Hz, 1H), 6.96(dd, J=2.0, 8.4 Hz, 1H).

Example 22 Ethyl(E)-3-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.31(t, J=6.5 Hz, 3H), 1.98(tt, J=6.0, 6.0Hz, 2H), 2.55(d, J=1.0 Hz, 3H), 2.77(t, J=6.0 Hz, 2H), 2.93(s, 3H),3.28(t, J=6.0 Hz, 2H), 4.19(q, J=6.5 Hz, 2H), 6.10(q, J=1.0 Hz, 1H),6.53(d, J=9.0 Hz, 1H), 7.18(d, J=2.0 Hz, 1H), 7.30(dd, J=9.02, 2.0 Hz,1H).

Example 23 Methyl(E,E,E)-7-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.93-2.02(m, 2H), 2.21(s, 3H), 2.38(bs, 3H),2.78(t, J=6.0 Hz, 2H), 2.92(s, 3H), 3.26(t, J=6.0 Hz, 2H), 3.71(s, 3H),5.77(s, 1H), 6.33(d, J=14.8 Hz, 1H), 6.51-6.56(m, 2H), 7.05(dd, J=11.6,15.2 Hz, 1H), 7.16(d, J=2.4 Hz, 1H), 7.24-7.27(m, 1H).

Example 24(E,E,E)-7-(1-Methyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.99(tt, J=6.0, 6.0 Hz, 2H), 2.21(s, 3H),2.39(s, 3H), 2.78(t, J=6.0 Hz, 2H), 2.92(s, 3H), 3.26(t, J=6.0 Hz, 2H),5.80(s, 1H), 6.35(d, J=15.0 Hz, 1H), 6.55(d, J=12.5 Hz, 1H), 6.55(d,J=8.5 Hz, 1H), 7.10(dd, J=15.0, 12.5 Hz, 1H), 7.15(d, J=2.0 Hz 1H),7.26(dd, J=2.0, 8.5 Hz, 1H).

Example 25 Ethyl(E)-3-(1-cyclohexyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.10-1.53(m, 8H), 1.66-1.92(m, 7H), 2.55(d,J=0.8 Hz, 3H), 2.73(t, J=6.0 Hz, 2H), 3.24(t, J=6.0 Hz, 2H),3.55-3.65(m, 1H), 4.10-4.20(m, 2H), 6.08(q, J=1.2 Hz, 1H), 6.60(d, J=9.2Hz, 1H), 7.17(d, J=2.4 Hz, 1H), 7.27(dd, J=2.4, 8.4 Hz, 1H).

Example 26 Methyl(E,E,E)-7-(1-cyclohexyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.10-1.56(m, 5H), 1.66-1.92(m, 7H), 2.20(d,J=0.8 Hz, 3H), 2.38(d, J=0.8 Hz, 3H), 2.74(t, J=6.0 Hz, 2H), 3.23(t,J=5.6 Hz, 2H), 3.55-3.65(m, 1H), 3.71(s, 3H), 5.77(s, 1H), 6.32(d,J=15.2 Hz, 1H), 6.53(bd, J=11.2 Hz, 1H), 6.61(d, J=9.2H, 1H), 7.06(dd,J=10.8, 14.8 Hz, 1H), 7.14(d, J=2.4 Hz, 1H), 7.23(dd, J=2.4, 8.4 Hz,1H).

Example 27(E,E,E)-7-(1-Cyclohexyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.10-1.54(m, 5H), 1.66-1.94(m, 7H), 2.21(s,3H), 2.39(s, 3H), 2.74(t, J=6.0 Hz, 2H), 3.23(t, J=6.0 Hz, 2H),3.55-3.65(m, 1H), 5.79(s, 1H), 6.34(d, J=14.8 Hz, 1H), 6.54(d, J=11.6Hz, 1H), 6.61(d, J=9.2 Hz, 1H), 7.10(dd, J=11.2, 14.4 Hz, 1H), 7.14(d,J=2.0 Hz, 1H), 7.23-7.26(m, 1H).

Example 28 Ethyl(E)-3-[1-(1-methylethyl)-8-chloro-1,2,3,4-tetrahydroquinolin-6-yl]-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.06(t, J=6.8 Hz, 3H), 1.16(d, J=6.8 Hz, 6H),1.84(tt, J=6.0, 6.0 Hz, 2H), 2.10(d, J=4.4 Hz, 3H), 2.68(t, J=6.0 Hz,2H), 3.14(t, J=6.0 Hz, 2H), 4.08(q, J=6.8 Hz, 2H), 4.12(hept., J=6.8 Hz,1H), 6.70-6.72(m, 1H), 6.99(d, J=2.0 Hz, 1H).

Example 29 Methyl(E,E,E)-7-[1-(1-methylethyl)-8-chloro-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=6.8 Hz, 6H), 1.86(tt, J=6.0, 6.0Hz, 2H), 2.09(d, J=4.0 Hz, 3H), 2.19(s, 3H), 2.70(t, J=6.0 Hz, 1H),3.16(t, J=6.0 Hz, 2H), 3.71(s, 3H), 4.16(hept., J=6.8 Hz, 1H), 5.86(s,1H), 6.52(s, 1H), 6.56(dd, J=14.8, 27.6 Hz, 1H), 6.77-6.79(m, 1H),7.06(d, J=2.4 Hz, 1H).

Example 30(E,E,E)-7-[1-(1-Methylethyl)-8-chloro-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=6.8 Hz, 6H), 1.83-1.90(m, 2H),2.10(d, J=3.6 Hz, 3H), 2.19(s, 3H), 2.70(t, J=6.8 Hz, 2H), 3.16(t, J=6.0Hz, 2H), 4.16(hept., J=6.8 Hz, 1H), 5.88(s, 1H), 6.55(s, 1H), 6.59(dd,J=15.6, 32.4 Hz, 1H), 6.77-6.79(m, 1H), 7.06(d, J=2.4 Hz, 1H).

Example 31 Ethyl(E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-pentenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.13(t, J=7.6 Hz, 3H), 1.20(d, J=6.4 Hz, 6H),1.30(t, J=6.8 Hz, 3H), 1.90(tt, J=6.0, 6.0 Hz, 2H), 2.74(t, J=6.0 Hz,2H), 3.08(q, J=7.6 Hz, 2H), 3.20(t, J=6.0 Hz, 2H), 4.15(hept., J=6.4 Hz,1H), 4.18(q, J=7.2 Hz, 2H), 6.00(s, 1H), 6.64(d, J=9.2 Hz, 1H), 7.17(d,J=2.4 Hz, 1H), 7.27(dd, J=2.8, 9.2 Hz, 1H).

Example 32 Methyl(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-3-methyl-nona-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.11(t, J=7.6 Hz, 3H), 1.19(d, J=6.4 Hz, 6H),1.91(tt, J=6.0, 6.0 Hz, 2H), 2.38(d, J=0.8 Hz, 3H), 2.68(q, J=7.6 Hz,2H), 2.75(t, J=6.0 Hz, 2H), 3.19(t, J=6.0 Hz, 2H), 3.71(s, 3H),4.14(hept., J=6.4 Hz, 1H), 5.76(s, 1H), 6.32(d, J=15.2 Hz, 1H), 6.42(d,J=11.2 Hz, 1H), 6.65(d, J=8.8 Hz, 1H), 7.03(dd, J=11.2, 15.2 Hz, 1H),7.12(d, J=2.4 Hz, 1H), 7.21(dd, J=2.4, 8.8 Hz, 1H).

Example 33(E,E,E)-7-[1-(1-Methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-3-methyl-nona-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.10(t, J=7.6 Hz, 3H), 1.18(d, J=6.4 Hz, 6H),1.90(tt, J=6.0, 6.0 Hz, 2H), 2.38(bs, 3H), 2.68(q, J=7.6 Hz, 2H),2.73(t, J=6.0 Hz, 2H), 3.18(t, J=6.0 Hz, 2H), 4.12(hept., J=6.4 Hz, 1H),5.80(bs, 1H), 6.34(bd, J=16.0 Hz, 1H), 6.43(d, J=12.6 Hz, 1H), 6.64(d,J=8.8 Hz, 1H), 6.92-7.08(m, 1H), 7.12(bs, 1H), 7.21(dd, J=2.4, 8.8 Hz,1H).

Example 34 Ethyl(E)-3-[1-(1-methylethyl)-8-chloro-1,2,3,4-tetrahydroquinolin-6-yl]-2-fluoro-2-pentenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.00 (t, J=7.6 Hz, 3H), 1.11(t, J=7.2 Hz,3H), 1.17(d, J=6.8 Hz, 6H), 1.89(tt, J=6.0, 6.0 Hz, 2H), 2.51(dq, J=3.5,7.6 Hz, 2H), 2.71(t, J=6.0 Hz, 2H), 3.15(t, J=6.0 Hz, 2H), 4.09(q, J=7.2Hz, 2H), 4.10(hept., J=6.8 Hz, 1H), 6.61(d, J=8.4 Hz, 1H), 6.75(d, J=2.0Hz, 1H), 6.85(dd, J=2.0, 8.4 Hz, 1H).

Example 35 Methyl(E,E,E)-7-[1-(1-methylethyl)-8-chloro-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-nona-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 0.99(t, J=7.6 Hz, 3H), 1.19(d, J=6.8 Hz, 6H),1.83-1.90(m, 2H), 2.17(s, 3H), 2.52(dq, J=3.2, 7.6 Hz, 2H), 2.70(t,J=6.8 Hz, 2H), 3.16(t, J=6.0 Hz, 2H), 3.70(s, 3H), 4.15(hept., J=6.8 Hz,1H), 5.85(s, 1H), 6.47(dd, J=15.8, 44.0 Hz, 1H), 6.50(d, J=2.4 Hz, 1H),6.74(d, J=2.0 Hz, 1H), 7.03(d, J=2.0 Hz, 1H).

Example 36(E,E,E)-7-[1-(1-Methylethyl)-8-chloro-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-nona-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 0.99(t, J=7.6 Hz, 3H), 1.19(d, J=6.8 Hz, 6H),1.80-1.92(m, 2H), 2.17(s, 3H), 2.48-2.56(m, 2H), 2.70(t, J=6.0 Hz, 2H),3.16(t, J=6.0 Hz, 2H), 4.16(hept., J=6.8 Hz, 1H), 5.87(s, 1H), 6.51(dd,J=16.0, 38.0 Hz, 1H), 6.53(s, 1H), 6.75(d, J=2.0 Hz, 1H), 7.03(d, J=2.0Hz, 1H).

Example 37 Ethyl(E)-3-[1-(1-methylethyl)-8-methoxy-1,2,3,4-tetrahydroquinolin-6-yl]-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.05(t, J=7.2 Hz, 3H), 1.12(d, J=6.8 Hz, 6H),1.82(tt, J=6.0, 6.0 Hz, 2H), 2.12(d, J=4.4 Hz, 3H), 2.67(t, J=6.0 Hz,2H), 3.14(t, J=6.0 Hz, 2H), 3.79(s, 3H), 4.06(q, J=7.2 Hz, 2H),4.13(hept., J=6.4 Hz, 1H), 6.47(d, J=1.6 Hz, 1H), 6.49(d, J=2.0 Hz, 1H).

Example 38 Methyl(E,E,E)-7-[1-(1-methylethyl)-8-methoxy-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.15(d, J=6.8 Hz, 6H), 1.84(tt, J=6.0, 6.0Hz, 2H), 2.13(d, J=3.16 Hz, 3H), 2.17(s, 3H), 2.69(t, J=6.0 Hz, 2H),3.16(t, J=6.0 Hz, 2H), 3.70(s, 3H), 3.80(s, 3H), 4.18(hept., J=6.8 Hz,1H), 5.84(s, 1H), 6.50(d, J=15.6 Hz, 1H), 6.54(bs, 2H), 6.64(dd, J=15.6,26.4 Hz, 1H).

Example 39(E,E,E)-7-[1-(1-Methylethyl)-8-methoxy-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.15(d, J=6.8 Hz, 6H), 1.80-1.88(m, 2H),2.14(d, J=3.2 Hz, 3H), 2.17(s, 3H), 2.70(t, J=6.0 Hz, 2H), 3.16(t, J=6.0Hz, 2H), 3.81(s, 3H), 4.18(hept., J=6.8 Hz, 1H), 6.53(d, J=15.6 Hz, 1H),6.54(bs, 2H), 6.68(dd, J=15.6, 26.4 Hz, 1H).

Example 40 Ethyl(E)-3-[1-(1-methylethyl)-2,3,4,5-tetrahydro-1H-benzazepin-7-yl]-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.09(t, J=7.2 Hz, 3H), 1.22(d, J=6.8 Hz, 6H),1.60-1.70(m, 4H), 2.12(d, J=4.8 Hz, 3H), 2.70-2.78(m, 2H), 2.92-2.99(m,2H), 4.09(hept., J=6.8 Hz, 1H), 4.10(q, J=7.2 Hz, 2H), 6.80-6.98(m, 3H).

Example 41 Ethyl(E,E,E)-7-[1-(1-methylethyl)-2,3,4,5-tetrahydro-1H-benzazepin-7-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.24(d, J=6.4 Hz, 6H), 1.60-1.73(m, 4H),2.13(d, J=3.6 Hz, 3H), 2.19(bs, 3H), 2.73-2.76(m, 2H), 2.94-3.04(m, 2H),3.70(s, 3H), 3.78(hept., J=6.4 Hz, 1H), 5.85(s, 1H), 6.51(d, J=15.6 Hz,1H), 6.64(dd, J=15.6, 26.0 Hz, 1H), 6.89(d, J=8.0 Hz, 1H), 6.98-7.01(m,2H).

Example 42(E,E,E)-7-[1-(1-Methylethyl)-2,3,4,5-tetrahydro-1H-benzazepin-7-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.24(d, J=6.4 Hz, 6H), 1.60-1.76(m, 4H),2.14(d, J=3.2 Hz, 3H), 2.20(bs, 3H), 2.70-2.80(m, 2H), 2.93-3.03(m, 2H),3.78(hept., J=6.4 Hz, 1H), 5.87(s, 1H), 6.53(d, J=16.0 Hz, 1H), 6.67(dd,J=15.6, 26.4 Hz, 1H), 6.90(d, J=8.0 Hz, 1H), 6.98-7.01(m, 2H).

Example 43 Ethyl(Z)-3-[1-(1-methylethyl)-2,3,4,5-tetrahydro-1H-benzazepin-7-yl]-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.23(d, J=6.4 Hz, 6H), 1.37(t, J=7.2 Hz, 3H),1.60-1.70(m, 4H), 2.43(d, J=3.6 Hz, 3H), 2.72-2.80(m, 2H), 2.96-3.03(m,2H), 3.79(hept., J=6.4 Hz, 1H), 4.32(q, J=7.2 Hz, 2H), 6.88(d, J=8.8 Hz,1H), 7.19-7.23(m, 2H).

Example 44 Methyl(E,E,Z)-7-[1-(1-methylethyl)-2,3,4,5-tetrahydro-1H-benzazepin-7-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.23(d, J=6.8 Hz, 6H), 1.62-1.73(m, 4H),2.14(d, J=2.4 Hz, 3H), 2.37(s, 3H), 2.72-2.80(m, 2H), 2.93-3.05(m, 2H),3.73(s, 3H), 3.78(hept., J=6.8 Hz, 1H), 5.88(s, 1H), 6.59(d, J=15.2 Hz,1H), 6.82(dd, J=15.2, 26.0 Hz, 1H), 6.89(d, J=8.4 Hz, 1H), 7.23-7.27(m,2H).

Example 45(E,E,Z)-7-[1-(1-Methylethyl)-2,3,4,5-tetrahydro-1H-benzazepin-7-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.23(d, J=6.4 Hz, 6H), 1.62-1.75(m, 4H),2.15(d, J=2.4 Hz, 3H), 2.38(s, 3H), 2.72-2.80(m, 2H), 2.95-3.05(m, 2H),3.79(hept., J=6.4 Hz, 1H), 5.92(s, 1H), 6.62(d, J=15.2 Hz, 1H), 6.86(dd,J=15.2, 26.0 Hz, 1H), 6.89(d, J=8.4 Hz, 1H), 7.24-7.29(m, 2H).

Example 46 Ethyl(E)-3-[1-(1-methylethyl)-1,2,3,4,5,6-hexahydrobenzazocin-8-yl]-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.03(t, J=7.2 Hz, 3H), 1.07(d, J=6.0 Hz, 6H),1.11-1.17(m, 2H), 1.55-1.68(m, 4H), 2.14(d, J=4.4 Hz, 3H), 2.75-2.83(m,4H), 3.28(hept., J=6.0 Hz, 4.04(q, J=6.8 Hz, 2H), 6.97(d, J=2.0 Hz, 1H),6.99(dd, J=2.4, 8.0 Hz, 1H), 7.14(d, J=8.0 Hz, 1H).

Example 47 Methyl(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4,5,6-hexahydrobenzazocin-8-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.08(d, J=6.4 Hz, 6H), 1.10-1.19(m, 2H),1.57-1.67(m, 4H), 2.14(s, 3H), 2.15(d, J=4.0 Hz, 3H), 2.77-2.82(m, 4H),3.29(hept., J=6.4 Hz, 1H), 3.70(s, 3H), 5.85(s, 1H), 6.51(s, 1H);6.54(d, J=11.6 Hz, 1H), 7.04(d, J=2.0 Hz, 1H), 7.06(dd, J=2.0, 8.0 Hz,1H), 7.18(d, J=8.4 Hz, 1H).

Example 48(E,E,E)-7-[1-(1-Methylethyl)-1,2,3,4,5,6-hexahydrobenzazocin-8-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.09(d, J=6.4 Hz, 6H), 1.09-1.19(m, 2H),1.56-1.68(m, 4H), 2.15(s, 3H), 2.16(d, J=3.6 Hz, 3H), 2.76-2.87(m, 4H),3.30(hept., J=6.4 Hz, 1H), 5.87(s, 1H), 6.54(s, 1H), 6.57(d, J=15.6 Hz,1H), 7.04(d, J=2.0 Hz, 1H), 7.07(dd, J=2.0, 8.0 Hz, 1H), 7.18(d, J=8.0Hz, 1H).

Example 49 Ethyl(E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-7-yl]-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.20(d, J=6.4 Hz, 6H), 1.32(t, J=7.2 Hz, 3H),1.90(tt, J=6.0, 6.0 Hz, 2H), 2.55(d, J=1.6 Hz, 3H), 2.74(t, J=6.0 Hz,2H), 3.17(t, J=6.0 Hz, 2H), 4.15(hept., J=6.4 Hz, 1H), 4.21(q, J=7.2 Hz,2H), 6.09(q, J=1.2 Hz, 1H), 6.66(dd, J=1.6, 7.6 Hz, 1H), 6.74(d, J=1.2Hz, 1H), 6.94(d, J=7.6 Hz, 1H).

Example 50 Methyl(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-7-yl]-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.20(d, J=6.4 Hz, 6H), 1.91(tt, J=6.0, 6.0Hz, 2H), 2.23(d, J=1.6 Hz, 3H) 2.39(d, J=1.2 Hz, 3H), 2.73(t, J=6.0 Hz,2H), 3.17(t, J=6.0 Hz, 2H), 3.72(s, 3H), 4.17(hept., J=6.8 Hz, 1H),5.80(s, 1H), 6.36(d, J=15.2 Hz, 1H), 6.52(bd, J=11.2 Hz, 1H), 6.67(dd,J=2.0, 7.6 Hz, 1H), 6.76(d, J=1.2 Hz, 1H), 7.04(dd, J=11.2, 14.8 Hz,1H).

Example 51(E,E,E)-7-[1-(1-Methylethyl)-1,2,3,4-tetrahydroquinolin-7-yl]-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.21(d, J=6.4 Hz, 6H), 1.90(tt, J=6.0, 6.0Hz, 2H), 2.24(s, 3H), 2.39(s, 3H), 2.73(t, J=6.0 Hz, 2H), 3.17(t, J=6.0Hz, 2H), 4.17(hept., J=6.4 Hz, 1H), 5.82(s, 1H), 6.39(d, J=15.2 Hz, 1H),6.53(d, J=12.0 Hz, 1H), 6.67(dd, J=1.6, 7.6 Hz, 1H), 6.76(s, 1H),6.93(d, J=7.8 Hz, 1H), 7.08(dd, J=11.6, 15.6 Hz, 1H)

Example 52 Ethyl(E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-7-yl]-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.08(t, J=7.2 Hz, 3H), 1.16(d, J=6.8 Hz, 6H),1.89(tt, J=6.0, 6.0 Hz, 2H), 2.12(d, J=4.4 Hz, 3H), 2.72(t, J=6.0 Hz,2H), 3.14(t, J=6.0 Hz, 2H), 4.04(hept., J=6.8 Hz, 1H), 4.08(q, J=7.2 Hz,2H), 6.35(dd, J=2.0, 7.2 Hz, 1H), 6.45(bs, 1H), 6.90(d, J=7.6 Hz, 1H).

Example 53 Methyl(E,E,E)-7-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-7-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.18(d, J=6.8 Hz, 6H), 1.91(tt, J=6.0, 6.0Hz, 2H), 2.13(d, J=3.6 Hz, 3H), 2.18(d, J=0.8 Hz, 3H), 2.74(t, J=6.0 Hz,2H), 3.18(t, J=6.0 Hz, 2H), 3.70(s, 3H), 4.06(hept., J=6.8 Hz, 1H),5.85(s, 1H), 6.43(dd, J=1.6, 7.6 Hz, 1H), 6.52(d, J=15.6 Hz, 1H),6.52(bs, 1H), 6.67(dd, J=16.0, 26.4 Hz, 1H), 6.93(d, J=7.6 Hz, 1H).

Example 54(E,E,E)-7-[1-(1-Methylethyl)-1,2,3,4-tetrahydroquinolin-7-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.18(d, J=6.8 Hz, 6H), 1.86-1.95(m, 2H),2.14(d, J=3.6 Hz, 3H), 2.18(bs, 3H), 2.75(t, J=6.0 Hz, 2H), 3.18(t,J=6.0 Hz, 2H), 4.06(hept., J=6.8 Hz, 1H), 5.87(bs, 1H), 6.43(bd, J=7.2Hz, 1H), 6.52-6.56(m, 2H), 6.70(dd, J=15.6, 26.0 Hz, 1H), 6.93(d, J=7.6Hz, 1H).

Example 55 Ethyl(E)-3-(2,3,6,7-tetrahydro-1H,5H-benzo[I,J]quinolizin-9-yl)-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.30(t, J=6.8 Hz, 3H), 1.97(tt, J=6.4, 5.6Hz, 4H), 2.53(d, J=1.2 Hz, 3H), 2.75(t, J=6.4 Hz, 4H), 3.19(t, J=5.6 Hz,4H), 4.18(q, J=7.2 Hz, 2H), 6.07(q, J=1.2 Hz, 1H), 7.02(s, 2H).

Example 56 Methyl(E,E,E)-7-(2,3,6,7-tetrahydro-1H,5H-benzo[I,J]quinolizin-9-yl]-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.97(tt, J=6.4, 5.6 Hz, 4H), 2.18(s, 3H),2.38(s, 3H), 2.76(t, J=6.4 Hz), 3.17(t, J=6.4 Hz, 4H), 3.71(s, 3H),5.76(s, 1H), 6.32(d, J=14.8 Hz, 1H), 6.51(d, J=10.8 Hz, 1H), 6.98(s,2H), 7.05(dd, J=11.2, 15.2 Hz, 1H).

Example 57(E,E,E)-7-(2,3,6,7-Tetrahydro-1H,5H-benzo[I,J]quinolizin-9-yl)-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.97(tt, J=6.4, 5.6 Hz, 4H), 2.19(s, 3H),2.38(s, 3H), 2.76(t, J=6.4 Hz, 4H), 3.17(t, J=5.6 Hz, 4H), 5.79(s, 1H),6.34(d, J=14.8 Hz, 1H), 6.52(d, J=11.2 Hz, 1H), 6.99(s, 2H), 7.09(dd,J=11.6, 15.2 Hz, 1H).

Example 58 Ethyl(E)-3-(2,3,6,7-tetrahydro-1H,5H-benzo[I,J]quinolizin-9-yl]-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.15(t, J=7.2 Hz, 3H), 1.93-2.05(m, 4H),2.10(d, J=4.8 Hz, 3H), 2.72(t, J=6.0 Hz, 4H), 3.14(t, J=6.0 Hz, 4H),4.12(q, J=7.2 Hz, 2H), 6.64(s, 2H).

Example 59 Methyl(E,E,E)-7-(2,3,6,7-tetrahydro-1H,5H-benzo[I,J]quinolizin-9-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.98(tt, J=6.0, 6.0 Hz, 4H), 2.09(d, J=3.6Hz, 3H), 2.20(d, J=0.8 Hz, 3H), 2.75(t, J=6.4 Hz, 4H), 3.17(t, J=6.0 Hz,4H), 3.70(s, 3H), 5.84(s, 1H), 6.48(d, J=16.0 Hz, 1H), 6.67(dd, J=16.0,26.4 Hz, 1H), 6.69(s, 2H).

Example 60(E,E,E)-7-(2,3,6,7-Tetrahydro-1H,5H-benzo[I,J]quinolizin-9-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.98(tt, J=6.0, 6.0 Hz, 4H), 2.16(d, J=3.6Hz, 3H), 2.21(s, 3H), 2.75(t, J=6.4 Hz, 4H), 3.18(t, J=6.0 Hz, 4H),5.86(s, 1H), 6.51(d, J=16.0 Hz, 1H), 6.71(dd, J=16.0, 26.4 Hz, 1H),6.69(s, 2H).

Example 61 Ethyl(E)-3-[1,4-di(1-methylethyl)-1,2,3,4-tetrahydroquinoxalin-6-yl]-2-butenoat

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=6.5 Hz, 6H), 1.20(d, J=6.5 Hz, 6H),1.31(t, J=6.5 Hz, 3H), 2.56(bs, 3H), 3.00-3.40(m, 4H), 4.00-4.30(m, 2H),4.19(q, J=6.5 Hz, 2H), 5.98-6.15(m, 1H), 6.53-6.68(m, 1H), 6.75-7.00(m,2H).

Example 62 Methyl(E,E,E)-7-[1,4-di(1-methylethyl)-1,2,3,4-tetrahydroquinoxalin-6-yl]-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.19(d, J=6.5 Hz, 6H), 1.20(d, J=6.5 Hz, 6H),2.22(s, 3H), 2.38(s, 3H), 3.15-3.21(m, 2H), 3.22-3.28(m, 2H), 3.71(s,3H), 5.77(s, 1H), 6.32(d, J=15.0 Hz, 1H), 6.51(d, J=11.0 Hz, 1H),6.60(d, J=8.0 Hz, 1H), 6.80(s, 1H), 6.83(d, J=8.5 Hz, 1H), 7.06(dd,J=11.0, 15.0 Hz, 1H).

Example 63(E,E,E)-7-[1,4-Di(1-methylethyl)-1,2,3,4-tetrahydroquinoxalin-6-yl]-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.15(d, J=6.5 Hz, 6H), 1.19(d, J=6.5 Hz, 6H),2.18(bs, 3H), 2.33(bs, 3H), 3.10-3.35(m, 4H), 3.95-4.23(m, 2H), 5.81(bs,1H), 6.32(d, J=15.0 Hz, 1H), 6.49(d, J=11.0 Hz, 1H), 6.58(d, J=8.0 Hz,1H), 6.75-6.85(m, 2H), 6.90-7.13(m, 1H).

Example 64 Ethyl(E)-3-[1,4-di(1-methylethyl)-1,2,3,4-tetrahydroquinoxalin-6-yl]-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.12(t, J=7.2 Hz, 3H), 1.16(d, J=6.8 Hz, 3H),1.17(d, J=6.8 Hz, 3H), 2.12(d, J=4.4 Hz, 3H), 3.16-3.24(m, 4H),4.00-4.13(m, 4H), 6.45(d, J=1.6 Hz, 1H), 6.49(dd, J=1.6, 10.0 Hz, 1H),6.57(d, J=8.4 Hz, 1H).

Example 65 Methyl(E,E,E)-7-[1,4-di(1-methylethyl)-1,2,3,4-tetrahydroquinoxalin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.18(d, J=6.4 Hz, 3H), 1.20(d, J=6.4 Hz, 3H),2.13(bs, 3H), 2.19(s, 3H), 3.14-3.28(m, 4H), 3.70(s, 3H), 3.98-4.12(m,2H), 5.84(s, 1H), 6.48-6.78(m, 5H).

Example 66(E,E,E)-7-[1,4-Di(1-methylethyl)-1,2,3,4-tetrahydroquinoxalin-6-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.18(d, J=6.4 Hz, 3H), 1.20(d, J=6.4 Hz, 3H),2.14(d, J=3.6 Hz, 3H), 2.20(bs, 3H), 3.18-3.29(m, 4H), 3.97-4.12(m, 2H),5.86(s, 1H), 6.50-6.63(m, 4H), 6.76(dd, J=15.6, 26.0 Hz, 1H).

Example 67 Ethyl(E)-3-[4-(1-methylethyl)-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.13(t, J=7.2 Hz, 3H), 1.17(d, J=6.4 Hz, 6H),2.10(d, J=4.8 Hz, 3H), 3.24(t, J=4.8 Hz, 2H), 4.11(q, J=7.2 Hz, 2H),4.22(t, J=4.4 Hz, 2H), 6.65-6.69(m, 3H).

Example 68 Methyl(E,E,E)-7-[4-(1-methylethyl)-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.20(d, J=6.8 Hz, 6H), 2.10(d, J=3.6 Hz, 3H),2.20(s, 3H), 3.26(t, J=4.8 Hz, 2H), 3.70(s, 3H), 4.11(hept., J=6.8 Hz,1H), 4.24(t, J=4.8 Hz, 2H), 5.84(s, 1H), 6.50(d, J=15.2 Hz, 1H),6.59-6.72(m, 4H).

Example 69(E,E,E)-7-[1-(4-Methylethyl)-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.21(d, J=6.8 Hz, 6H), 2.11(d, J=3.6 Hz, 3H),2.21(s, 3H), 3.27(t, J=4.8 Hz, 2H), 4.11(hept., J=6.8 Hz, 1H), 4.24(t,J=4.8 Hz, 2H), 5.86(s, 1H), 6.53(d, J=15.6 Hz, 1H), 6.63-6.74(m, 4H).

Example 70 Ethyl (E)-3-[1-(1-methylethyl)indol-5-yl]-2-butenoate

¹ H-NMR(400 MHz, CDCl) δ: 1.33(t, J=7.0 Hz, 3H), 1.54(d, J=6.5 Hz, 6H),2.67(d, J=1.0 Hz, 3H), 4.22(q, J=7.0 Hz, 2H), 4.68(hept., J=6.5 Hz, 1H),6.20(q, J=1.0 Hz, 1H), 6.54(d, J=3.0 Hz, 1H), 7.25(d, J=3.0 Hz, 1H),7.34-7.40(m, 2H), 7.80(d, J=1.15 Hz, 1H).

Example 71(E,E,E)-7-[1-(1-Methylethyl)-indol-5-yl]-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.53(d, J=6.5 Hz, 6H), 2.34(s, 3H), 2.41(s,3H), 4.66(hept., J=6.5 Hz, 1H), 5.84(s, 1H), 6.40(d, J=15.0 Hz, 1H),6.52(d, J=2.5 Hz, 1H), 6.64(d, J=11.0 Hz, 1H), 7.12(dd, J=15.0, 11.0 Hz,1H), 7.22(d, J=3.0 Hz, 1H), 7.33-7.41(m, 2H), 7.75(bs, 1H).

Example 72 Ethyl(E)-3-[1-(1-methylethyl)-indol-5-yl]-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.00(t, J=7.2 Hz, 3H), 1.53(d, J=6.4 Hz, 6H),2.21(d, J=4.4 Hz, 3H), 4.05(q, J=6.8 Hz, 2H), 4.67(hept., J=6.4 Hz, 1H),6.49(d, J=3.2 Hz, 1H), 7.03(dd, J=2.0, 8.8 Hz, 1H), 7.22(d, J=3.2 Hz,1H), 7.34(d, J=8.8 Hz, 1H), 7.44(d, J=2.0 Hz, 1H).

Example 73 Methyl(E,E,E)-7-[1-(1-methylethyl)-indol-5-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.56(d, J=6.8 Hz, 6H), 2.13(d, J=0.8 Hz, 3H),2.21(d, J=3.6 Hz, 3H), 3.69(s, 3H), 4.69(hept., J=6.8 Hz, 1H), 5.84(s,1H), 6.52(d, J=3.2 Hz, 1H), 6.54(d, J=16.0 Hz, 1H), 6.60(dd, J=16.0,26.4 Hz, 1H), 7.09(dd, J=1.6, 8.8 Hz, 1H), 7.26(d, J=3.2 Hz, 1H),7.37(d, J=8.8 Hz, 1H), 7.50(d, J=1.6 Hz, 1H).

Example 74(E,E,E)-7-[1-(1-Methylethyl)-indol-5-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.56(d, J=6.8 Hz, 6H), 2.13(bs, 3H), 2.22(d,J=2.8 Hz, 3H), 4.69(hept., J=6.8 Hz, 1H), 5.87(s, 1H), 6.52-6.69(m, 3H),7.09(bd, J=9.2 Hz, 1H), 7.26(bs, 1H), 7.37(bd, J=11.2 Hz, 1H), 7.50(bs,1H).

Example 75 Ethyl (E)-3-(3-methyl-4-dimethylamino-phenyl)-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.31(t, J=7.1 Hz, 3H), 2.34(s, 3H), 2.56(t,J=1.2 Hz, 3H), 2.73(s, 6H), 4.20(q, J=7.1 Hz, 2H), 6.11(q, J=1.2 Hz,1H), 6.98(d, J=8.4 Hz, 1H), 7.29-7.32(m, 2H).

Example 76 Methyl(E,E,E)-7-(3-methyl-4-dimethylaminophenyl)-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 2.23(s, 3H), 2.34(s, 3H), 2.38(s, 3H),2.72(s, 6H), 3.72(s, 3H), 5.80(s, 1H), 6.36(d, J=15.0 Hz, 1H), 6.55(d,J=11.0 Hz, 1H), 6.98(d, J=8.4 Hz, 1H), 7.03(dd, J=11.0, 15.0 Hz, 1H),7.26-7.34(m, 2H).

Example 77(E,E,E)-7-(3-Methyl-4-dimethylamino-phenyl)-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 2.24(s, 3H), 2.34(s, 3H), 2.39(s, 3H),2.72(s, 6H), 5.83(s, 1H), 6.39(d, J=15.0 Hz, 1H), 6.57(d, J=11.0 Hz,1H), 6.99(d, J=8.0 Hz, 1H), 7.08(dd, J=11.0, 15.0 Hz, 1H), 7.24-7.34(m,3H).

Example 78 Ethyl(E)-3-(3-(1-methylethyl)-4-dimethylaminophenyl)-2-fluoro-2-butenoate

¹ H-NMR(400 MHz, CDCl₃) δ: 0.98(t, J=7.2 Hz, 3H), 1.20(d, J=7.2 Hz, 6H),2.13(d, J=4.8 Hz, 3H), 2.67(s, 6H), 3.50(hept., J=7.2 Hz, 1H), 4.02(q,J=7.2 Hz, 2H), 6.95(dd, J=2.0 Hz, 8.0 Hz, 1H), 7.03(d, J=2.0 Hz, 1H),7.05(d, J=8.0 Hz, 1H).

Example 79 Methyl(E,E,E)-7-[3-(1-methylethyl)-4-dimethylaminophenyl]-6-fluoro-3-methyl-octa-2,4,6-trienoate

¹ H-NMR(400 MHz, CDCl₃) δ: 1.22(d, J=6.8 Hz, 6H), 2.15(d, J=4.0 Hz, 3H),2.17(s, 3H), 2.70(s, 6H), 3.52(hept., J=6.8 Hz, 1H), 3.70(s, 3H),5.86(s, 1H), 6.54(s, 1H), 6.58(dd, J=14.9, 33.4 Hz, 1H), 7.04(dd, J=2.4,8.4 Hz, 1H), 7.06(d, J=8.4 Hz, 1H), 7.11(d, J=2.4 Hz, 1H).

Example 80(E,E,E)-7-[3-(1-Methylethyl)-4-dimethylaminophenyl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid

¹ H-NMR(400 MHz, CDCl₃) δ: 1.22(d, J=6.8 Hz, 6H), 2.16(d, J=3.6z, 3H),2.18(s, 3H), 2.71(s, 6H), 3.53(hept., J=6.4 Hz, 1H), 5.88(s, 1H),6.58(s, 1H), 6.61(dd, J=15.6, 41.6 Hz, 1H), 7.05(dd, J=2.4, 8.8 Hz, 1H),7.09(d, J=8.8 Hz, 1H), 7.11(d, J=2.4 Hz, 1H).

The structures of the compounds prepared in Examples 7 to 80 are shownin Tables 2 to 9.

                  TABLE 2                                                         ______________________________________                                          Ex. 7                                                                               #STR66##                                                                 - Ex. 8                                                                            #STR67##                                                                 - Ex. 9                                                                            #STR68##                                                                 - Ex. 10                                                                           #STR69##                                                                 - Ex. 11                                                                           #STR70##                                                                 - Ex. 12                                                                           #STR71##                                                                 - Ex. 13                                                                           #STR72##                                                                 - Ex. 14                                                                           #STR73##                                                                 - Ex. 15                                                                           #STR74##                                                                 - Ex. 16                                                                          ##STR75##                                                              ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                          Ex. , 17                                                                           #STR76##                                                               Ex. , 18                                                                       ##ST 77##                                                                       - Ex. , 19                                                                        #STR78##                                                                  - Ex. , 20                                                                        #STR79##                                                                  - Ex. , 21                                                                        #STR80##                                                                  - Ex. , 22                                                                        #STR81##                                                                  - Ex. , 23                                                                        #STR82##                                                                  - Ex. , 24                                                                        #STR83##                                                                  - Ex. , 25                                                                        #STR84##                                                                  - Ex. , 26                                                                       ##STR85##                                                               ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                          Ex. 27                                                                              #STR86##                                                              Ex. 28                                                                         ##STR 7##                                                                       - Ex. 29                                                                           #STR88##                                                                 - Ex. 30                                                                           #STR89##                                                                 - Ex. 31                                                                           #STR90##                                                                 - Ex. 32                                                                           #STR91##                                                                 - Ex. 33                                                                           #STR92##                                                                 - Ex. 34                                                                           #STR93##                                                                 - Ex. 35                                                                           #STR94##                                                                 - Ex. 36                                                                          ##STR95##                                                              ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                          Ex. , 37                                                                           #STR96##                                                               Ex. , 38                                                                       ##ST 97##                                                                       - Ex. , 39                                                                        #STR98##                                                                  - Ex. , 40                                                                        #STR99##                                                                  - Ex. , 41                                                                        #STR100##                                                                 - Ex. , 42                                                                        #STR101##                                                                 - Ex. , 43                                                                        #STR102##                                                                 - Ex. , 44                                                                        #STR103##                                                                 - Ex. , 45                                                                        #STR104##                                                                 - Ex. , 46                                                                       ##STR105##                                                              ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                          Ex. 47                                                                              #STR106##                                                             Ex. 48                                                                         ##STR 07##                                                                      - Ex. 49                                                                           #STR108##                                                                - Ex. 50                                                                           #STR109##                                                                - Ex. 51                                                                           #STR110##                                                                - Ex. 52                                                                           #STR111##                                                                - Ex. 53                                                                           #STR112##                                                                - Ex. 54                                                                           #STR113##                                                                - Ex. 55                                                                           #STR114##                                                                - Ex. 56                                                                          ##STR115##                                                             ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                          Ex. 57                                                                              #STR116##                                                             Ex. 58                                                                         ##STR 17##                                                                      - Ex. 59                                                                           #STR118##                                                                - Ex. 60                                                                           #STR119##                                                                - Ex. 61                                                                           #STR120##                                                                - Ex. 62                                                                           #STR121##                                                                - Ex. 63                                                                           #STR122##                                                                - Ex. 64                                                                           #STR123##                                                                - Ex. 65                                                                           #STR124##                                                                - Ex. 66                                                                          ##STR125##                                                             ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                          Ex. 67                                                                              #STR126##                                                             Ex. 68                                                                         ##STR 27##                                                                      - Ex. 69                                                                           #STR128##                                                                - Ex. 70                                                                           #STR129##                                                                - Ex. 71                                                                           #STR130##                                                                - Ex. 72                                                                           #STR131##                                                                - Ex. 73                                                                           #STR132##                                                                - Ex. 74                                                                           #STR133##                                                                - Ex. 75                                                                           #STR134##                                                                - Ex. 76                                                                          ##STR135##                                                             ______________________________________                                    

                  TABLE 9                                                         ______________________________________                                          Ex. 77                                                                               #STR136##                                                            Ex. 78                                                                         ##STR1 7##                                                                      - Ex. 79                                                                            #STR138##                                                               - Ex. 80                                                                           ##STR139##                                                            ______________________________________                                    

Example 81(E,E,E)-6-Fluoro-7-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalinyl)]-3-methyl-octa-2,4,6-trienoicacid ##STR140## Step 1 Ethyl(E)-2-fluoro-3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalinyl)]-2-butenoate##STR141##

186 mg of sodium hydride was suspended in 10 ml ofN,N-dimethylformamide. A solution of 0.94 ml of ethyl2-fluoro-diethylphosphonoacetate in 5 ml of N,N-dimethylformamide wasdropped into the obtained suspension in a nitrogen stream at 0° C.,followed by the stirring for 30 minutes. A solution of 540 mg of2-acetyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-quinoxaline in 10 ml ofN,N-dimethylformamide was dropped into the mixture prepared above. Themixture thus obtained was stirred for one hour, followed by the additionof a saturated aqueous solution of ammonium chloride. The resultingmixture was extracted with ethyl acetate. The organic phase was washedwith water and a saturated aqueous solution of common salt successively,dried over anhydrous magnesium sulfate and concentrated in a vacuum. Theobtained residue was subjected to silica gel column chromatography(developer: 2% ethyl acetate/n-hexane) to give 290 mg of the titlecompound as a colorless oil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.01(t, J=7.2Hz, 3H), 1.30(s, 6H), 1.33(s,6H), 1.80(s, 4H), 2.19(d, J=4.2Hz, 3H), 4.07(q, J=7.2Hz, 2H), 8.24(s,1H).

Step 2

(E)-2-Fluoro-3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalinyl)]-2-butenal##STR142##

290 mg of ethyl(E)-2-fluoro-3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalinyl)]-2-butenoatewas dissolved in 15 ml of tetrahydrofuran. 2.9 ml of diisobutylaluminumhydride (1.5 M toluene solution) was dropped into the solution preparedabove in a nitrogen stream at -78° C. The mixture thus obtained wasstirred for 2 hours. The reaction was stopped by the addition of asaturated aqueous solution of ammonium chloride, followed by theextraction with ethyl acetate. The organic phase was washed with waterand a saturated aqueous solution of common salt successively, dried overanhydrous magnesium sulfate and concentrated in a vacuum to give 270 mgof a colorless oil. Then, a solution of 1.4 ml of dimethyl sulfoxide in4 ml of dichloromethane was dropped into a solution of 0.85 ml of oxalylchloride in 40 ml of dichloromethane in a nitrogen stream at -60° C.,followed by the stirring for 5 minutes. A solution of 270 mg of thecolorless oil prepared above in 10 ml of dichloromethane was droppedinto the obtained mixture. The mixture thus obtained was stirred for 15minutes, followed by the dropwise addition of 6.5 ml of triethylamine.The obtained mixture was stirred for 5 minutes, and the temperature ofthe mixture was raised to room temperature. The resulting mixture wasstirred for 15 minutes, followed by the addition of water. The obtainedmixture was extracted with dichloromethane. The organic phase was washedwith water and a saturated aqueous solution of common salt successively,dried over anhydrous magnesium sulfate and concentrated in a vacuum. Theobtained residue was subjected to silica gel column chromatography(developer: 5% ethyl acetate/n-hexane) to give 230 mg of the titlecompound as a yellow solid.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.32(s, 6H), 1.35(s, 6H), 1.83(s, 4H),2.36(d, J=4.0Hz, 3H), 8.47(s, 1H), 9.70(d, J=19.0Hz, 1H).

Step 3

(E,E,E)-6-Fluoro-7-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalinyl)]-3-methyl-octa-2,4,6-trienoicacid ##STR143##

65 mg of metallic sodium was added to methanol to prepare a methanolicsolution of sodium methoxide. This solution was concentrated in a vacuumand suspended in 10 ml of N,N-dimethylformamide. 0.89 g of triethyl3-methyl-4-phosphonocrotonate and a solution of 230 mg of(E)-2-fluoro-3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalinyl)]-2-butenalin 10 ml of N,N-dimethylformamide were added to the obtained suspensionsuccessively in a nitrogen stream at 0° C. The obtained mixture wasstirred for 30 minutes, followed by the addition of a saturated aqueoussolution of ammonium chloride. The obtained mixture was extracted withethyl acetate. The organic phase was washed with water and a saturatedaqueous solution of common salt successively, dried over anhydrousmagnesium sulfate and concentrated in a vacuum. The obtained residue wassubjected to silica gel column chromatography (developer: 5% ethylacetate/n-hexane) to give 220 mg of a pale-yellow solid. This solid washydrolyzed in a similar manner to that described in Step 4 of Example 2to give 60 mg of the title compound as a light-brown solid.

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.27(s, 6H), 1.29(s, 6H), 1.76(s, 4H),2.16(s, 3H), 2.20(bs, 3H), 6.00(s, 1H), 6.76(d, J=15.2Hz, 1H), 7.26(dd,J=15.2, 30.5Hz, 1H), 8.58(s, 1H).

Example 82(E,E,Z)-6-Fluoro-7-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalinyl)]-3-methyl-octa-2,4,6-trienoicacid ##STR144## Step 1 Ethyl(Z)-2-fluoro-3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalinyl)]-2-butenoate##STR145##

165 mg of the title compound was obtained as a colorless oil in asimilar manner to that described in Step 1 of Example 81 through silicagel column chromatography.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.31(s, 6H), 1.34(s, 6H), 1.39(t, J=7.2Hz,3H), 1.80(s, 4H), 2.50(d, J=3.6Hz, 3H), 4.36(q, J=7.2Hz, 2H), 8.65(d,J=3.6Hz, 1H).

Step 2

(E,E,Z)-6-Fluoro-7-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalinyl)]-3-methyl-octa-2,4,6-trienoicacid ##STR146##

The title compound was obtained as a pale-yellow solid in a similarmanner to that described in Steps 2 and 3 of Example 81.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.32(s, 6H), 1.34(s, 6H), 1.80(s, 4H),2.25(d, J=2.2Hz, 3H), 2.40(s, 3H), 5.99(s, 1H), 6.76(d, J=15.6Hz, 1H),6.90(dd, J=15.6, 26.4Hz, 1H), 8.79(d, J=2.7Hz, 1H).

Example 83(E,E,Z)-7-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethylquinoxalinyl)]-3-methyl-octa-2,4,6-trienoicacid ##STR147## Step 1 Ethyl(Z)-3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalinyl)]-2-butenoate

48 mg of sodium hydride was suspended in 10 ml of N,N-dimethylformamide,and 0.36 ml of ethyl diethyl-phosphonoacetate was dropped into thesuspension in a nitrogen stream at 0° C. The obtained mixture wasstirred for 30 minutes, followed by the dropwise addition of a solutionof 140 mg of 2-acetyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalinein 10 ml of N,N-dimethylformamide. The obtained mixture was heated to60° C. and stirred for 48 hours, followed by the addition of a saturatedaqueous solution of ammonium chloride. The obtained mixture wasextracted with ethyl acetate. The organic phase was washed with waterand a saturated aqueous solution of common salt successively, dried overanhydrous magnesium sulfate and concentrated in a vacuum. The obtainedresidue was subjected to silica gel column chromatography (developer: 2%ethyl acetate/n-hexane) to give 120 mg of the title compound as acolorless oil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.32(s, 6H), 1.33(s, 6H), 1.34(t, J=7.1Hz,3H), 1.80(s, 4H), 2.61(d, J=1.3Hz, 3H), 4.24(q, J=7.1Hz, 2H), 6.75(q,J=1.3Hz, 1H), 8.58(s, 1H). ##STR148## Step 2(E,E,Z)-7-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethylquinoxalinyl)]-3-methyl-octa-2,4,6-trienoicacid ##STR149##

The title compound was obtained in a similar manner to that described inSteps 2 and 3 of Example 81.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.29(s, 6H), 1.32(s, 6H), 1.78(s, 4H),2.32(s, 3H), 2.40(s, 3H), 5.89(s, 1H), 6.54(d, J=15.0Hz, 1H), 7.12(dd,J=12.1, 15.0Hz, 1H), 7.23(d, J=12.1Hz, 1H), 8.55(s, 1H).

Example 84(E,E)-5-[3-(7,8,9,10-Tetrahydro-7,7,10,10-tetramethylphenazinyl)]-3-methyl-2,4-pentadienoicacid ##STR150## Step 17,6,9,10-Tetrahydro-7,7,10,10-tetramethylphenazine-3-carbaldehyde##STR151##

1.17 g of methyl7,8,9,10-tetrahydro-7,7,10,10-tetramethyl-3-phenazinecarboxylate wasdissolved in 50 ml of tetrahydrofuran. 10.5 ml of diisobutylaluminumhydride (1.5M toluene solution) was dropped into the solution in anitrogen stream at -78° C., followed by the stirring for 30 minutes. Asaturated aqueous solution of ammonium chloride was added to thereaction mixture to stop the reaction, followed by the extraction withethyl acetate. The organic phase was washed with water and a saturatedaqueous solution of common salt successively, dried over anhydrousmagnesium sulfate and concentrated in a vacuum to give a colorless oil.This oil was dissolved in 10 ml of dichloromethane, followed by theaddition of 5.0 g of manganese dioxide. The obtained mixture was stirredovernight and filtered through Celite. The filtrate was concentrated ina vacuum to give 0.83 g of the title compound as a pale-yellow solid.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.45(s, 12H), 1.93(s, 4H), 8.07(d, J=8.8Hz,1H), 8.13(dd, J=1.8, 8.6Hz, 1H), 8.48(d, J=1.8Hz, 1H), 10.22(s, 1H).

Step 2

(E,E)-5-[3-(7,8,9,10-Tetrahydro-7,7,10,10-tetramethylphenazinyl)]-3-methyl-2,4-pentadienoicacid ##STR152##

The title compound was prepared in a similar manner to that described inStep 3 of Example 81.

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.36(s, 6H), 1.37(s, 6H), 1.86(s, 4H),2.34(s, 3H), 6.04(s, 1H), 7.23(d, J=16.0Hz, 1H), 7.33(d, J=16.0Hz, 1H),7.92(d, J=8.8Hz, 1H), 8.02(dd, J=1.3, 8.8Hz, 1H), 8.12(d, J=1.3Hz, 1H).

Example 85 Ethyl (E)-3-[6-(2,3-diisopropylquinoxalinyl)]-2-butenoate##STR153## Step 1 2,3-Diisopropylquinoxaline-6-ethanone ##STR154##

The title compound was prepared by the use of2,3-diisopropyl-6-quinoxalinal in a similar manner to that described inSteps 3 and 4 of Example 1.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.36-1.42(m, 12H), 2.77(s, 3H), 3.48-3.60(m,2H), 8.04(d, J=8.8Hz, 1H), 8.23(dd, J=2.2, 8.8Hz, 1H), 8.58(d, J=2.2Hz,1H).

Step 2

Ethyl (E)-3-[6-(2,3-diisopropylquinoxalinyl)]-2-butenoate ##STR155##

The title compound was prepared in a similar manner to that described inStep 1 of Example 83.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.34(t, J=7.1Hz, 3H), 1.38(d, J=6.6Hz, 6H),1.39(d, J=6.8Hz, 6H), 2.70(d, J=1.3Hz, 3H), 3.54(hept., J=6.8Hz, 2H),4.24(q, J=7.1Hz, 2H), 6.33(d, J=1.3Hz, 1H), 7.77(dd, J=2.2, 8.8Hz, 1H),7.97(d, J=8.8Hz, 1H), 8.12(d, J=2.2Hz, 1H).

Example 86(E,E,E)-7-[6-(2,3-Diisopropylquinoxalinyl)]-3-methyl-octa-2,4,6-trienoicacid ##STR156## Step 1 (E)-3-[6-(2,3-Diisopropylquinoxalinyl)]-2-butenal##STR157##

The title compound was prepared by the use of ethyl(E)-3-[6-(2,3-diisopropylquinoxalinyl)]-2-butenoate in a similar mannerto that described in Step 1 of Example 84.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.39(d, J=6.6Hz, 6H), 1.40(d, J=6.8Hz, 6H),2.70(d, J=1.3Hz, 3H), 3.50-3.60(m, 2H), 6.57(dd, J=1.3, 7.6Hz, 1H),7.82(dd, J=2.0, 8.8Hz, 1H), 1.01(d, J=8.8Hz, 1H), 8.20(d, J=2.0Hz, 1H),10.25(d, J=7.6Hz, 1H).

Step 2

(E,E,E)-7-[6-(2,3-Diisopropylquinoxalinyl)]-3-methyl-octa-2,4,6-trienoicacid ##STR158##

The title compound was prepared in a similar manner to that described inStep 3 of Example 81.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.39(d, J=6.6Hz, 6H), 1.40(d, J=6.8Hz, 6H),2.40(s, 3H), 2.42(s, 3H), 3.48-3.59(m, 2H), 5.89(s, 1H), 6.49(d,J=14.7Hz, 1H), 6.83(d, J=10.5Hz, 1H), 7.14(dd, J=10.5, 14.7Hz, 1H),7.85(dd, J=2.2, 8.8Hz, 1H), 7.95(d, J=8.8Hz, 1H), 8.07(d, J=2.2Hz, 1H).

The following compounds were prepared in a similar manner to thatdescribed above.

Example 87(E,E,Z)-7-[2-(5,5,7,7-Tetramethylcyclopenta[b]pyrazinyl)]-3-methyl-octa-2,4,6-trienoicacid ##STR159##

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.28(s, 6H), 1.29(s, 6H), 1.96(s, 2H),2.28(s, 3H), 2.30(s, 3H), 5.87(s, 1H), 6.65(d, J=14.8Hz, 1H), 7.11(dd,J=10.8, 14.8Hz, 1H), 7.31(d, J=10.8Hz, 1H), 8.65(s, 1H).

Example 88(E,E)-5-[3-(7,8,9,10-Tetrahydrophenazinyl)]-3-methyl-2,4-pentadienoicacid ##STR160##

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.92-1.98(m, 4H), 2.35(s, 3H), 3.02-3.07(m,4H), 6.03(s, 1H), 7.23(d, J=15.5Hz, 1H), 7.29(d, J=15.5Hz, 1H), 7.89(d,J=8.6Hz, 1H), 8.02(dd, J=1.9, 86Hz, 1H), 8.07(d, J=1.9Hz, 1H).

Example 89(E,E)-5-[6-(2,3-Diethylquinoxalinyl)]-3-methyl-2,4-pentadienoic acid##STR161##

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.32(t, J=7.3Hz, 3H), 1.33(t, J=7.3Hz, 3H),2.35(s, 3H), 3.00(q, J=7.3Hz, 2H), 3.01(q, J=7.3Hz, 2H), 6.04(s, 1H),7.23(d, J=16.3Hz, 1H), 7.30(d, J=16.1Hz, 1H), 7.94(d, J=8.6Hz, 1H),8.01(dd, J=1.6, 8.6Hz, 1H), 8.13(d, J=1.3Hz, 1H), 12.19(bs, 1H)

Example 90(E,E)-5-[6-(2,3-Diisopropylquinoxalinyl)]-3-methyl-2,4-pentadienoic acid##STR162##

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.37(d, J=6.8Hz, 12H), 2.46(s, 3H),3.48-3.60(m, 2H), 6.01(s, 1H), 7.03(d, J=16.1Hz, 1H), 7.16(d, J=16.1Hz,1H), 7.80(dd, J=2.0, 8.4Hz, 1H), 7.97(d, J=8.8Hz, 1H), 8.05(d, J=1.8Hz,1H).

Example 91(E,E)-5-[6-[2,3-Di(3-pentyl)quinoxalinyl]]-3-methyl-2,4-pentadienoicacid ##STR163##

¹ H-NMR(400 MHz, DMSO-d₆) δ: 0.78(t, J=7.3Hz, 12H), 1.64-1.76(m, 4H),1.80-1.89(m, 4H), 2.34(s, 3H), 3.13-3.22(m, 2H), 6.05(s, 1H), 7.25(d,J=16.0Hz, 1H), 7.33(d, J=16.0Hz, 1H), 7.94(d, J=8.8Hz, 1H), 8.01(dd,J=1.6, 8.8Hz, 1H), 8.14(d, J=1.6Hz, 1H).

Example 92(E,E)-5-[6-(2,3-Dicyclopropylquinoxalinyl)]-3-methyl-2,4-pentadienoicacid ##STR164##

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.06-1.18(m, 4H), 2.32(s, 3H), 2.68-2.76(m,2H), 6.01(s, 1H), 7.18(d, J=16.2Hz, 1H), 7.26(d, J=16.2Hz, 1H), 7.79(d,J=8.6Hz, 1H), 7.89-7.93(m, 1H), 7.99(bs, 1H)

Example 93(E,E)-5-[6-(2,3-Dicyclobutylquinoxalinyl)]-3-methyl-2,4-pentadienoicacid ##STR165##

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.80-1.90(m, 2H), 2.00-2.15(m, 2H),2.27-2.50(m, 8H), 3.86-3.96(m, 2H), 6.05(s, 1H), 7.24(d, J=16.4Hz, 1H),7.33(d, J=16.0Hz, 1H), 7.97(d, J=8.8Hz, 1H), 8.02(dd, J=1.2, 8.8Hz, 1H),8.18(s, 1H).

Example 94(E,E)-5-[6-(2,3-Dicyclopentylquinoxalinyl)]-3-methyl-2,4-pentaenoic acid##STR166##

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.64-1.74(m, 4H), 1.75-1.88(m, 4H),1.88-1.95(m, 4H), 1.99-2.09(m, 2H), 2.34(s, 3H), 3.64-3.73(m, 2H),6.04(s, 1H), 7.23(d, J=16.0Hz, 1H), 7.30(d, J=16.4Hz, 1H), 7.90(d,J=8.8Hz, 1H), 7.99(dd, J=1.6, 8.8Hz, 1H), 8.10(d, J=1.6Hz, 1H).

Example 95(E,E)-5-[6-(2,3-Dicyclohexylquinoxalinyl)]-3-methyl-2,4-pentadienoicacid ##STR167##

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.23-1.36(m, 2H), 1.38-1.52(m, 4H),1.60-1.89(m, 12H), 2.34(s, 3H), 3.07-3.18(m, 2H), 6.04(s, 1H), 7.21(d,J=16.1Hz, 1H), 7.30(d, J=16.1Hz, 1H), 7.90(d, J=8.6Hz, 1H), 7.99(dd,J=1.3, 8.6Hz, 1H), 8.11(d, J=1.3Hz, 1H).

Example 96(E,E)-5-[6-[2,3-Di(2-furyl)quinoxalinyl]]-3-methyl-2,4-pentadienoic acid##STR168##

¹ H-NMR(400 MHz, DMSO-d₆) δ: 2.16(s, 3H), 5.85(s, 1H), 6.68-6.78(m, 4H),7.32(d, J=15.0Hz, 1H), 7.91(bs, 2H), 8.01-8.04(m, 1H), 8.10(d, J=8.6Hz,1H), 8.14(bs, 1H), 8.53(d, J=15.0Hz, 1H)

Example 97(E,E)-5-[9-(2,2,6,6-Tetramethylthiepa[4,5-b]quinoxalinyl)]ethyl-2,4-pentadienoicacid ##STR169##

¹ H-NMR(400 MHz, CDCl₃) δ: 1.61(s, 12H), 2.47(s, 3H), 2.92(s, 4H),6.02(s, 1H), 7.01(d, J=16.2Hz, 1H), 7.16(d, J=16.2Hz, 1H), 7.78-7.83(m,1H), 7.91(d, J=8.8Hz, 1H), 7.98(bs, 1H).

Example 98(E,E)-5-[2-(3,6,6,9,9-Pentamethylcyclo-hexa[g]quinoxalinyl)]-3-methyl-2,4-pentadienoicacid ##STR170##

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.35(s, 12H), 1.72(s, 4H), 2.39(s, 3H),2.76(s, 3H), 6.13(s, 1H), 7.34(d, J=15.0Hz, 1H), 7.60(d, J=15.0Hz, 1H),7.89(s, 1H), 7.94(s, 1H).

Preparative Example 11,4-Dimethyl-1,2,3,4-tetrahydroquinoline-6-carbaldehyde ##STR171##

The title compound was prepared from1,4-dimethyl-1,2,3,4-tetrahydroquinoline in a similar manner to thatdescribed in Step 2 of Example 1.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.30(d, J=7.2Hz, 3H), 1.66-1.74(m, 1H),1.95-2.03(m, 1H), 2.86-2.94(m, 1H), 3.02(s, 3H), 3.33-3.46(m, 2H),6.57(d, J=9.2Hz, 1H), 7.55-7.58(m, 2H) , 9.68(s, 1H)

Preparative Example 21-(1,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)ethanone ##STR172##

In a similar manner to that described in Steps 3 and 4 of Example 1, thetitle compound was prepared from1,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbaldehyde prepared inPreparative Example 1.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.29(d, J=6.8Hz, 3H), 1.66-1.74(m, 1H),1.95-2.03(m, 1H), 2.49(s, 3H), 2.86-2.96(m, 1H), 2.99(s, 3H),3.28-3.43(m, 2H), 6.51(d, J=8.8Hz, 1H), 7.60-7.72(m, 2H).

Example 99 Ethyl(E)-3-(1,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-butenoate##STR173##

In a similar manner to that described in Step 5 of Example 1, the titlecompound was prepared from1-(1,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)ethanone prepared inPreparative Example 2.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.29(t, J=7.2Hz, 3H), 1.32(d, J=6.8Hz, 3H),1.66-1.74(m, 1H), 1.98-2.06(m, 1H), 2.56(d, J=1.2Hz, 3H), 2.86-2.96(m,1H), 2.94(s, 3H), 3.20-3.36(m, 2H), 4.19(q, J=7.2Hz, 2H), 6.10(q,J=1.2Hz, 1H), 6.54(d, J=8.8Hz, 1H), 7.26(d, J=2.0Hz, 1H), 7.30(dd,J-2.0, 8.4Hz, 1H).

Preparative Example 3(E)-3-(1,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-butenal##STR174##

In a similar manner to that described in Steps 1 and 2 of Example 2, thetitle compound was prepared from ethyl(E)-3-(1,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-2-butenoateprepared in Example 99.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.29(d, J=6.8Hz, 3H), 1.68-1.76(m, 1H),1.98-2.04(m, 1H), 2.52(d, J=1.2Hz, 3H), 2.86-2.94(m, 1H), 2.97(s, 3H),3.24-3.40(m, 2H), 6.43(dd, J=1.2, 8.0Hz, 1H), 6.56(d, J=8.8Hz, 1H),7.26-7.35(m, 1H), 7.38-7.41(m, 1H), 10.11(d, J=8.0Hz, 1H).

Example 100 Methyl(E,E,E)-7-(1,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)ethyl-octa-2,4,6-trienoate ##STR175##

In a similar manner to that described in Step 3 of Example 2, the titlecompound was prepared from(E)-3-(1,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-butenal preparedin Preparative Example 3.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.30(d, J=7.2Hz, 3H), 1.66-1.75(m, 1H),1.98-2.06(m, 1H), 2.22(d, J=1.2Hz, 3H), 2.39(d, J=1.2Hz, 3H),2.86-2.96(m, 1H), 2.93(s, 3H), 3.18-3.34(m, 2H), 3.71(s, 3H), 5.77(bs,1H), 6.34(d, J=14.8Hz, 1H), 6.51-6.57(m, 2H), 7.06(dd, J=11.2, 15.2Hz,1H), 7.23-7.27(m, 2H).

Example 101(E,E,E)-7-(1,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-methyl-octa-2,4,6-trienoicacid ##STR176##

In a similar manner to that described in Step 4 of Example 2, the titlecompound was prepared from methyl(E,E,E)-7-(1,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-3-methyl-octa-2,4,6-trienoateprepared in Example 100.

¹ H-NMR(400 MHz, CDCl3) δ: 1.30(d, J=7.2Hz, 3H), 1.65-1.77(m, 1H),1.96-2.10(m, 1H), 2.22(s, 3H), 2.38(bs, 3H), 2.88-3.00(m, 1H), 2.93(s,3H), 3.15-3.35(m, 2H), 5.80(bs, 1H), 6.36(d, J=14.8Hz, 1H), 6.45-6.62(m,2H), 7.08(dd, J=10.8, 26.0Hz, 1H), 7.20-7.32(m, 2H).

Preparative Example 41,4,4-Trimethyl-1,2,3,4-tetrahydroquinoline-6-carbaldehyde ##STR177##

The title compound was prepared from1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline in a similar manner to thatdescribed in Step 2 of Example 1.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.30(s, 6H), 1.74(t, J=6.4Hz, 2H), 3.03(s,3H), 3.40(t, J=6.0Hz, 2H), 6.57(d, J=8.4Hz, 1H), 7.56(dd, J=2.0, 8.8Hz,1H), 7.70(d, J=2.0Hz, 1H), 9.68(s, 1H).

Example 102 Ethyl(E)-3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-2-butenoate##STR178##

In a similar manner to that described in Steps 3, 4 and 5 of Example 1,the title compound was prepared from1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline-6-carbaldehyde prepared inPreparative Example 4.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.30(s, 6H), 1.32(t, J=7.2Hz, 3H), 1.76(t,J=6.0Hz, 2H), 2.57(d, J=1.2Hz, 3H), 2.94(s, 3H), 3.29(t, J=6.0Hz, 2H),4.20(q, J=6.8Hz, 2H), 6.09(q, J=1.2Hz, 1H), 6.54(d, J=8.8Hz, 1H),7.29(dd, J=2.4, 8.4Hz, 1H), 7.39(d, J=2.4Hz, 1H).

Preparative Example 5(E)-3-(1,4,4-Trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-butenal##STR179##

In a similar manner to that described in Steps 1 and 2 of Example 2, thetitle compound was prepared from ethyl(E)-3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-2-butenoateprepared in Example 102.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.30(s, 6H), 1.76(t, J=6.0Hz, 2H), 2.53(d,J=0.8Hz, 3H), 2.98(s, 3H), 3.33(t, J=6.0Hz, 2H), 6.43(bd, J=9.2Hz, 1H),7.36-7.40(m, 1H), 7.49(d, J=2.4Hz, 1H), 10.12(d, J=9.2Hz, 1H).

Example 103 Methyl(E,E,E)-7-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-3-methyl-octa-2,4,6-trienoate##STR180##

In a similar manner to that described in Step 3 of Example 2, the titlecompound was prepared from(E)-3-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-butenalprepared in Preparative Example 5.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.31(s, 6H), 1.77(t, J=6.0Hz, 2H), 2.22(d,J=1.2Hz, 3H), 2.39(d, J=1.2Hz, 3H), 2.93(s, 3H), 3.27(t, J=6.0Hz, 2H),3.71(s, 3H), 5.78(s, 1H), 6.34(d, J=15.2Hz, 1H), 6.51-6.56(m, 2H),7.06(dd, J=10.8, 14.4Hz, 1H), 7.25(dd, J=2.4, 6.0Hz, 1H), 7.37(d,J=2.4Hz, 1H).

Example 104(E,E,E)-7-(1,4,4-Trimethyl-1,2,3,4-tetrahydroquinolin-yl)-3-methyl-octa-2,4,6-trienoicacid ##STR181##

In a similar manner to that described in Step 4 in Example 2, the titlecompound was prepared from methyl(E,E,E)-7-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-methyl-octa-2,4,6-trienoateprepared in Example 103.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.32(s, 6H), 1.77(t, J=6.0Hz, 2H), 2.23(bs,3H), 2.39(bs, 3H), 2.94(s, 3H), 3.27(t, J=6.0Hz, 2H), 5.80(s, 1H),6.37(d, J=15.2Hz, 1H), 6.51-6.57(m, 2H), 7.11(dd, J=11.2, 14.8Hz, 1H),7.24-7.27(m, 1H) , 7.38 (d, J=2.4Hz, 1H)

Preparative Example 61,5,5-Trimethyl-2,3,4,5-tetrahydro-1H-benzazepine-7-carbaldehyde##STR182##

The title compound was prepared from1,5,5-trimethyl-2,3,4,5-tetrahydro-1H-benzazepine in a similar manner tothat described in Step 2 of Example 1.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.39(s, 6H), 1.66(t, J=6.4Hz, 2H),1.78-1.86(m, 2H), 2.97(s, 3H), 3.05(t, J=5.6Hz, 2H), 6.95(d, J=8.4Hz,1H), 7.61(dd, J=2.0, 8.4Hz, 1H), 7.83(d, J=1.6Hz, 1H).

Preparative Example 71-(1,5,5-Trimethyl-2,3,4,5-tetrahydro-1H-benzazepin-7-yl)ethanone##STR183##

In a similar manner to that described in Steps 3 and 4 of Example 1, thetitle compound was prepared from1,5,5-trimethyl-2,3,4,5-tetrahydro-1H-benzazepine-7-carbaldehydeprepared in Preparative Example 6.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.39(s, 6H), 1.64(t, J=6.0Hz, 2H),1.77-1.84(m, 2H), 2.54(s, 3H), 2.94(s, 3H), 2.99(t, J=6.0Hz, 2H),6.90(d, J=8.4Hz, 1H), 7.72(dd, J=2.0, 8.4Hz, 1H), 7.97(d, J=2.4Hz, 1H).

Example 105 Ethyl(E)-3-(1,5,5-trimethyl-2,3,4,5-tetrahydro-1H-benzazepin-7-yl)-2-butenoate##STR184##

In a similar manner to that described in Step 5 of Example 1, the titlecompound was prepared from1-(1,5,5-trimethyl-2,3,4,5-tetrahydro-1H-benzazepin-7-yl)ethanoneprepared in Preparative Example 7.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.32(t, J=7.2Hz, 3H), 1.39(s, 6H),1.60-1.66(m, 2H), 1.75-1.85(m, 2H), 2.58(d, J=1.2Hz, 3H), 2.85-2.94(m,5H), 4.21(q, J=7.2Hz, 2H), 6.10(q, J=1.2Hz, 1H), 6.91(d, J=8.8Hz, 1H),7.30(dd, J=2.4, 8.4Hz, 1H), 7.47(d, J=2.4Hz, 1H).

Preparative Example 8(E)-3-(1,5,5-Trimethyl-2,3,4,5-tetrahydro-1H-benzazepin-7-yl)-2-butenal##STR185##

In a similar manner to that described in Steps 1 and 2 of Example 2, thetitle compound was prepared from ethyl(E)-3-(1,5,5-trimethyl-2,3,4,5-tetrahydro-1H-benzazepin-7-yl)-2-butenoateprepared in Example 105.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.38(s, 6H), 1.62-1.66(m, 2H), 1.77-1.84(m,2H), 2.55(d, J=0.8Hz, 3H), 2.90-2.97(m, 5H), 6.43(dq, J=1.2, 8.0Hz, 1H),6.93(d, J=8.4Hz, 1H), 7.36-7.40(m, 1H), 7.56(d, J=2.4Hz, 1H), 10.15(d,J=8.0Hz, 1H).

Example 106 Methyl(E,E,E)-7-(1,5,5-trimethyl-2,3,4,5-tetrahydro-1H-benzazepin-7-yl)-3-methyl-octa-2,4,6-trienoate##STR186##

In a similar manner to that described in Step 3 of Example 2, the titlecompound was prepared from(E)-3-(1,5,5-trimethyl-2,3,4,5-tetrahydro-1H-benzazepin-7-yl)-2-butenalprepared in Preparative Example 8.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.40(s, 6H), 1.60-1.65(m, 2H), 1.26-1.84(m,2H), 2.24(d, J=1.2Hz, 3H), 2.39(d, J=0.8Hz, 3H), 2.87-2.90(m, 5H),3.72(s, 3H), 5.80(s, 1H), 6.36(d, J=14.8Hz, 1H), 6.54(bd, J=10.8Hz, 1H),6.92(d, J=8.8Hz, 1H), 7.05(dd, J=15.2, 11.2Hz, 1H), 7.25-7.29(m, 1H),7.46(d, J=2.4Hz, 1H).

Example 107(E,E,E)-7-(1,5,5-Trimethyl-2,3,4,5-tetrahydro-1H-benzazepin-7-3-methyl-octa-2,4,6-trienoicacid ##STR187##

In a similar manner to that described in Step 4 of Example 2, the titlecompound was prepared from methyl(E,E,E)-7-(1,5,5-trimethyl-2,3,4,5-tetrahydro-1H-benzazepin-7-yl)-3-methyl-octa-2,4,6-trienoateprepared in Example 106.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.41(s, 6H), 1.60-1.67(m, 2H), 1.75-1.85(m,2H), 2.26(bs, 3H), 2.40(bs, 3H), 2.85-2.95(m, 5H), 5.82(s, 1H), 6.39(d,J=15.2Hz, 1H), 6.56(bd, 11.2Hz, 1H), 6.92(d, J=8.4Hz, 1H), 7.10(dd,J=11.2, 15.2Hz, 1H), 7.29(dd, J=2.0, 8.4Hz, 1H), 7.47(d, J=2.0Hz, 1H).

Preparative Example 9(E/Z)-3-[1-(1-Methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]cinnamaldehyde##STR188##

The same procedure as that described in Example 1 and Steps 1 and 2 ofExample 2 was repeated except that phenyl Grignard reagent(phenylmagnesium bromide) was used in Step 3 of Example 1 instead of themethyl Grignard reagent (methylmagnesium bromide). The title compoundwas obtained as an isomer mixture (isomers 1 and 2).

¹ H-NMR(400 MHz, CDCl₃) δ: 1.20(d, J=6.8Hz, 6H), 1), 1.23(d, J=6.8Hz,6H, 2, 1.84-1.94(m, 2H, 1+2), 2.68(t. J=6.4Hz, 2H, 1), 2.69-2.78(m, 2H,2), 3.23(t, J=6.0Hz, 2H, 1), 3.24-3.27(m, 2H, 2), 4.11-4.21(m, 1H,(1+2), 6.55(d, J=8.4Hz, 1H, 1), 6.60(d, J=9.6Hz, 1H, 2), 7.01-7.07(m,2H, 1+2), 7.30-7.32(m; 2H, 1+2), 7.41-7.44(m, 4H, 1+2), 9.31(d, J=8.4Hz,1H, 1), 9.62(d, J=8.0Hz, 1H, 2). (identified based on the ¹ H-NMR peaksassignable to the isomer 1 or 2)

Example 108(E,E,E/Z)-7-[1-(1-Methylethyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-7-phenyl-3-methyl-hepta-2,4,6-trienoicacid ##STR189##

(E/Z)-3-[1-(1-Methylethyl)-1,2,3,4-tetrahydro-quinolin-6-yl)cinnamaldehydeprepared in Preparative Example 9 was treated in a similar manner tothat described in Steps 3 and 4 of Example 2 to give the title compoundas an isomer mixture (isomers 1 and 2)

¹ H-NMR(400 MHz, CDCl₃) δ: 1.18(d, J=6.8Hz, 6H, 1), 1.23(d, J=6.8Hz,6H), 1.84-1.98(m, 2H, 1+2), 2.13(bs, 3H, 1), 2.26(bs, 3H, 2),2.62-2.78(m, 2H, (1+2), 3.16-3.25(m, 2H, 1+2), 4.06-4.20(m, 1H, 1+2),5.75(s, 1H, 1), 5.80(s, 1H, 2), 6.36-6.39(m, 1H, 1+2), 6.57-6.59(m, 1H,1+2), 6.62-6.68(m, 5H, 1+2), 6.92-7.00(m, 4H, 1+2). (identified based onthe ¹ H-NMR peaks assignable to the isomer 1 or 2)

Preparative Example 101-(1-Methylethyl)-2-methyl-indoline-5-carbaldehyde ##STR190##

The title compound was prepared from 1-(1-methylethyl)-2-methyl-indolinein a similar manner to that described in Step 2 of Example 1.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.28(d, J=6.4Hz, 3H), 1.29(d, J=6.8Hz, 3H),1.35(d, J=7.2Hz, 3H), 2.59(dd, J=5.2, 16.0Hz, 1H), 3.25(dd, J=10.0,16.4Hz, 1H9, 3.77(hept., J=6.8Hz, 1H), 4.05-4.10(m, 1H), 6.37(d,J=8.4Hz, 1H), 7.50-7.52(m, 2H), 9.61(s, 1H).

Preparative Example 11(E)-3-[1-(1-Methylethyl)-2-methyl-indol-5-yl]-2-fluoro-2-butenal##STR191##

The title compound was prepared from 1-(1-methylethyl)-2-methylindole ina similar manner to that described in Steps 1 to 4 of Example 1 andSteps 1 to 3 of Example 5.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.63(d, J=7.2Hz, 6H), 2.34(d, J=4.0Hz, 3H),2.46(d, J=0.8Hz, 3H), 4.68(hept., J=6.8Hz, 1H), 6.24(q, J=0.8Hz, 1H),7.04(dd, J=1.6, 8.4Hz, 1H), 7.45-7.49(m, 2H), 9.32(d, J=19.6Hz, 1H).

Example 109 Methyl(E,E,E)-7-[1-(1-methylethyl)-2-methyl-indol-5-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate##STR192##

In a similar manner to that described in Step 3 of Example 2, the titlecompound was prepared from(E)-3-[1-(1-methylethyl)-2-methyl-indol-5-yl]-2-fluoro-2-butenalprepared in Preparative Example 11.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.63(d, J=7.2Hz, 6H), 2.13(s, 3H), 2.20(d,J=4.0Hz, 3H), 2.46(s, 3H), 3.69(s, 3H), 4.67(hept., J=7.2Hz, 1H),5.84(s, 1H), 6.21(s, 1H), 6.52(d, J=15.2Hz, 1H), 6.63(dd, J=16.0,25.6Hz, 1H), 6.98(dd, J=1.6, 8.4Hz, 1H), 7.38(d, J=1.6Hz, 1H), 7.44(d,J=8.8Hz, 1H).

Example 110(E,E,E)-7-[1-(1-Methylethyl)-2-methyl-indol-5-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid ##STR193##

In a similar manner to that described in Step 4 of Example 2, the titlecompound was prepared from methyl(E,E,E)-7-[1-(1-methylethyl)-2-methyl-indol-5-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoateprepared in Example 109.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.63(d, J=7.2Hz, 6H), 2.14(s, 3H), 2.21(d,J=3.2Hz, 3H), 2.46(s, 3H), 4.66(hept., J=7.2Hz, 1H), 5.86(bs, 1H),6.21(bs, 1H), 6.55(d, J=15.6Hz, 1H), 6.66(dd, J=15.6, 25.6Hz, 1H),6.97-7.00(m, 1H), 7.38-7.46(m, 2H).

Preparative Example 121-(1-Methylethyl)-2,3-dimethyl-indoline-5-carbaldehyde ##STR194##

The title compound was prepared from1-(1-methylethyl)-2,3-dimethyl-indoline in a similar manner to thatdescribed in Step 2 of Example 1.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.10(d, J=6.4Hz, 3H), 1.26(d, J=6.8Hz, 3H),1.29(d, J=6.8Hz, 3H), 1.38(d, J=6.9Hz, 3H), 3.37(hept., J=7.2Hz, 1H),3.75-3.82(m, 1H), 4.00-4.07(m, 1H), 6.37(d, J=8.4Hz, 1H), 7.48-7.52(m,2H), 9.62 (s, 1H)

Preparative Example 131-[1-(1-Methylethyl)-2,3-dimethyl-indol-5-yl]ethanone ##STR195##

In a similar manner to that described in Steps 3 and 4 of Example 1, thetitle compound was prepared from1-(l-methylethyl)-2,3-dimethyl-indoline-5-carbaldehyde prepared inPreparative Example 12.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.61(d, J=7.2Hz, 6H) 2.28(s, 3H), 2.38(s,3H), 2.67(s, 3H), 4.67(hept., J=6.8Hz, 1H), 7.43(d, J=8.8Hz, 1H),7.77(dd, J=2.0, 8.8Hz, 1H), 8.16(d, J=2.0Hz, 1H).

Example 111 Ethyl(E)-3-[1-(1-methylethyl)-2,3-dimethyl-indol-5-yl]-2-fluoro-2-butenoate##STR196##

In a similar manner to that described in Step 1 of Example 5, the titlecompound was prepared from1-[1-(1-methylethyl)-2,3-dimethyl-indol-5-yl]ethanone prepared inPreparative Example 13.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.00(t, J=6.8Hz, 3H), 1.59(d, J=6.8Hz, 6H),2.21(s, 6H), 2.35(s, 3H), 4.05(q, J=7.2Hz, 2H), 4.64(hept., J=6.8Hz,1H), 6.92(dd, J=1.6, 8.4Hz, 1H), 7.25-7.29(m, 1H), 7.37(d, J=8.4Hz, 1H).

Preparative Example 14(E)-3-[1-(1-Methylethyl)-2,3-dimethylindol-5-yl]-2-fluoro-2-butenal##STR197##

In a similar manner to that described in Steps 1 and 2 of Example 2, thetitle compound was prepared from ethyl(E)-3-[1-(1-methylethyl)-2,3-dimethyl-indol-5-yl]-2-fluoro-2-butenoateprepared in Example 111.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.61(d, J=6.8Hz, 6H), 2.23(s, 3H), 2.36(s,3H), 2.37(s, 3H), 4.67(hept., J=6.8Hz, 1H), 7.04(dd, J=2.0, 8.4Hz, 1H),7.41-7.46(m, 2H), 9.32(d, J=19.6Hz, 1H)

Example 112 Methyl(E,E,E)-7-[1-(1-methylethyl)-2,3-dimethyl-indol-5-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoate##STR198##

In a similar manner to that described in Step 3 of Example 2, the titlecompound was prepared from(E)-3-[1-(1-methylethyl)-2,3-dimethyl-indol-5-yl]-2-fluoro-2-butenalprepared in Preparative Example 14.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.62(d, J=7.2Hz, 6H), 2.13(s, 3H), 2.22(s,6H), 2.38(s, 3H), 3.69(s, 3H), 4.66(hept., J=7.2Hz, 1H), 5.84(s, 1H),6.53(d, J=15.6Hz, 1H), 6.66(dd, J=15.6, 26.4Hz, 1H), 6.98(dd, J=1.6,8.4Hz, 1H), 7.35(d, J=2.0Hz, 1H), 7.41(d, J=8.4Hz, 1H).

Example 113(E,E,E)-7-[1-(1-Methylethyl)-2,3-dimethyl-indol-5-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid ##STR199##

In a similar manner to that described in Step 4 of Example 2, the titlecompound was prepared from methyl(E,E,E)-7-[1-(1-methylethyl)-2,3-dimethyl-indol-5-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoateprepared in Example 112.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.62(d, J=7.2Hz, 6H), 2.14(s, 3H), 2.22(s,6H), 2.38(s, 3H), 4.66(hept., J=7.2Hz, 1H), 5.86(s, 1H), 6.56(d,J=15.6Hz, 1H), 6.70(dd, J=15.6, 26.0Hz, 1H), 6.99(dd, J=1.6, 8.4Hz, 1H),7.35(d, J=1.6Hz, 1H), 7.42(d, J=8.4Hz, 1H).

Preparative Example 15 1,2,3-Trimethyl-indole-5-carbaldehyde ##STR200##

1,2,3-Trimethylindoline (21.5 g) was formulated in a similar manner tothat described in Step 2 of Example 1 to obtain 20.1 g of1,2,3-trimethylindoline-5-carbaldehyde. The obtained aldehyde (7.5 g)was dissolved in 200 ml of 1,4-dioxane, followed by the addition of 18 gof DDQ. The obtained mixture was heated under reflux for 2.5 hours,followed by the addition of 100 ml of toluene. Insolubles were filteredout and the organic phase was concentrated in a vacuum. The obtainedresidue was purified by flash column chromatography to give 900 mg ofthe title compound.

¹ H-NMR(400 MHz, CDCl₃) δ: 2.29(s, 3H), 2.37(s, 3H), 3.69(s, 3H),7.30(d, J=8.4Hz, 1H), 7.71(dd, J=0.8, 8.4Hz, 1H), 8.03(d, J=0.8Hz, 1H),10.02(s, 1H).

Preparative Example 16 1-(1,2,3-Trimethyl-indol-5-yl)ethanone ##STR201##

In a similar manner to that described in Steps 3 and 4 of Example 1, thetitle compound was prepared from 1,2,3-trimethyl-indole-5-carbaldehydeprepared in

Preparative Example 15

¹ H-NMR(400 MHz, CDCl₃) δ: 2.29(s, 3H), 2.36(s, 3H), 2.67(s, 3H),3.67(s, 3H), 7.23(d, J=8.8Hz, 1H), 7.82(dd, J=1.6, 8.8Hz, 1H), 8.16(d,J=1.6Hz, 1H).

Preparative Example 17 (E)-3-(1,2,3-Trimethyl-indol-5-yl)-2-butenal##STR202##

In a similar manner to that described in Step 5 of Example 1 and Steps 1and 2 of Example 2, the title compound was prepared from1-(1,2,3-trimethyl-indol-5-yl)ethanone prepared in Preparative Example16.

¹ H-NMR(400 MHz, CDCl₃) δ: 2.27(s, 3H), 2.36(s, 3H), 2.67(d, J=1.2Hz,3H), 3.66(s, 3H), 6.54(dq, J=1.2, 8.0Hz, 1H), 7.23(d, J=8.4Hz, 1H),7.41(dd, J=2.0, 8.8Hz, 1H), 7.74(d, J=1.6Hz, 1H), 10.18(d, J=8.4Hz, 1H).

Example 114 Methyl(E,E,E)-7-(1,2,3-trimethyl-indol-5-yl)-3-methyl-octa-2,4,6-trienoate##STR203##

In a similar manner to that described in Step 3 of Example 2, the titlecompound was prepared from (E)-3-(1,2,3-trimethyl-indol-5-yl)-2-butenalprepared in Preparative Example 17.

¹ H-NMR(400 MHz, CDCl₃) δ: 2.27(s, 3H), 2.34(s, 3H), 2.36(d, J=1.2Hz,3H), 2.41(d, J=0.8Hz, 3H), 3.65(s, 3H), 3.72(s, 3H), 5.80(s, 1H),6.39(d, J=14.8Hz, 1H), 6.65(dd, J=2.0, 11.2Hz, 1H), 7.11(dd, J=11.2,14.8Hz, 1H), 7.19(d, J=8.8Hz, 1H), 7.33(dd, J=2.0, 8.8Hz, 1H), 7.59(d,J=1.2Hz, 1H).

Example 115(E,E,E)-7-(1,2,3-Trimethyl-indol-5-yl)-3-methyl-octa-2,4,6-trienoic acid##STR204##

In a similar manner to that described in Step 4 of Example 2, the titlecompound was prepared from methyl(E,E,E)-7-(1,2,3-trimethyl-indol-5-yl)-3-methyl-octa-2,4,6-trienoateprepared in Example 114.

¹ H-NMR(400 MHz, CDCl₃) δ: 2.27(s, 3H), 2.35(s, 3H), 2.37(s, 3H),2.42(s, 3H), 3.65(s, 3H), 5.83(bs, 1H), 6.41(d, J=14.8Hz, 1H), 6.67(bd,J=11.2Hz, 1H), 7.10-7.20(m, 2H), 7.34(dd, J=1.6, 8.4Hz, 1H), 7.60(d,J=1.2Hz, 1H).

Preparative Example 17 1,2,3,3-Tetramethyl-indoline-5-carbaldehyde##STR205##

The title compound was prepared from 1,2,3,3-tetramethyl-indoline in asimilar manner to that described in Step 2 of Example 1.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.06(s, 3H), 1.18(d, J=6.4Hz, 3H), 1.29(s,3H), 2.81(s, 3H), 3.22(q, J=6.4Hz, 1H), 6.42(d, J=8.0Hz, 1H),7.53-7.58(m, 2H), 9.68(s, 1H).

Preparative Example 18 1-(1,2,3,4-Tetramethyl-indolin-5-yl)ethanone##STR206##

In a similar manner to that described in Steps 3 and 4 of Example 1, thetitle compound was prepared from1,2,3,3-tetramethyl-indoline-5-carbaldehyde prepared in PreparativeExample 17.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.05(s, 3H), 1.19(d, J=6.4Hz, 3H), 1.30(s,3H), 2.51(s, 3H), 2.79(s, 3H), 3.14(q, J=6.4Hz, 1H), 6.39(d, J=8.0Hz,1H), 7.65(d, J=1.6Hz, 1H), 7.76(dd, J=1.6, 8.0Hz, 1H).

Example 116 Ethyl (E)-3-(1,2,3,3-tetramethyl-indolin-5-yl)-2-butenoate##STR207##

In a similar manner to that described in Step 5 of Example 1, the titlecompound was prepared from 1-(1,2,3,4-tetramethyl-indolin-5-yl)ethanoneprepared in Preparative Example 18.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.03(s, 3H), 1.19(d, J=6.4Hz, 3H), 1.30(s,3H), 1.32(t, J=7.2Hz, 3H), 2.57(d, J=8.0Hz, 3H), 2.73(s, 3H), 2.99(q,J=6.4Hz, 1H), 4.20(q, J=7.2Hz, 2H), 6.10(q, J=1.0Hz, 1H), 6.45(d,J=8.4Hz, 1H), 7.20(d, J=2.0Hz, 1H), 7.31(dd, J=2.0, 8.4Hz, 1H).

Preparative Example 19(E)-3-(1,2,3,3-Tetramethyl-indolin-5-yl)-2-butenal ##STR208##

In a similar manner to that described in Steps 1 and 2 of Example 2, thetitle compound was prepared from ethyl(E)-3-(1,2,3,3-tetramethyl-indolin-5-yl)-2-butenoate prepared in Example116.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.04(s, 3H), 1.19(d, J=6.4Hz, 3H), 1.30(s,3H), 2.53(d, J=O.8Hz, 3H), 2.76(s, 3H), 3.07(q, J=6.4Hz, 1H), 6.43(dq,J=1.0, 8.4Hz, 1H), 6.46(d, J=8.0Hz, 1H), 7.28(d, J=2.0Hz, 1H), 7.41(dd,J=2.0, 8.4Hz, 1H), 10.12(d, J=8.4Hz, 1H).

Example 117 Methyl(E,E,E)-7-(1,2,3,3-tetramethyl-indolin-5-yl)-3-methyl-octa-2,4,6-trienoate##STR209##

In a similar manner to that described in Step 3 of Example 2, the titlecompound was prepared from(E)-3-(1,2,3,3-tetramethyl-indolin-5-yl)-2-butenal prepared inPreparative Example 19.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.04(s, 3H), 1.19(d, J=6.4Hz, 3H), 1.31(s,3H), 2.23(d, J=1.2Hz, 3H), 2.39(d, J=1.2Hz, 3H), 2.72 (s, 3H), 2.94 (q,J=6.4Hz, 1H), 3.71(s, 3H), 5.78(bs, 1H), 6.35(d, J=14.8Hz, 1H), 6.46(d,J=8.0Hz, 1H), 6.54(d, J=10.4Hz, 1H), 7.06(dd, J=11.6, 15.6Hz, 1H),7.19(d, J=2.0Hz, 1H), 7.26(dd, J=2.0, 8.0Hz, 1H).

Example 118(E,E,E)-7-(1,2,3,3-Tetramethyl-indolin-5-yl)-3-methyl-octa-2,4,6-trienoicacid ##STR210##

In a similar manner to that described in Step 4 of Example 2, the titlecompound was prepared from methyl(E,E,E)-7-(1,2,3,3-tetramethyl-indolin-5-yl)-3-methyl-octa-2,4,6-trienoateprepared in Example 117.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.04(s, 3H), 1.19(d, J=6.4Hz, 3H), 1.31(s,3H), 2.24(s, 3H), 2.40(d, J=1.2Hz, 3H), 2.73(s, 3H), 2.95(q, J=6.4Hz,1H), 5.81(s, 1H), 6.38(d, J=15.2Hz, 1H), 6.47(d, J=8.4Hz, 1H), 6.56(bd,J=10.8Hz, 1H), 7.07-7.14 (m, 1H), 7.19(d, J=1.6Hz, 1H), 7.25-7.29(m,1H).

Example 119 Ethyl(E)-3-(1,2,3,4-tetramethyl-indolin-5-yl)-2-fluoro-2-butenoate ##STR211##

In a similar manner to that described in Step 1 of Example 5, the titlecompound was prepared from 1-(1,2,3,4-tetramethyl-indolin-5-yl)ethanoneprepared in Preparative Example 18.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.0l(s, 3H), 1.04(t, J=7.2Hz, 3H), 1.18(d,J=6.8Hz, 3H), 1.26(s, 3H), 2.13(d, J=4.8Hz, 3H), 2.70(s, 3H), 2.92(q,J=6.8Hz, 1H), 4.02-4.08(m, 2H), 6.44(d, J=8.0Hz, 1H), 6.82(d, J=2.0Hz,1H), 6.92(dd, J=2.0, 8.0Hz, 1H).

Preparative Example 20(E)-3-(1,2,3,3-Tetramethyl-indolin-5-yl)-2-fluoro-2-butenal ##STR212##

In a similar manner to that described in Steps 1 and 2 of Example 2, thetitle compound was prepared from ethyl(E)-3-(1,2,3,4-tetramethyl-indolin-5-yl)-2-fluoro-2-butenoate preparedin Example 119.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.04(s, 3H), 1.20(d, J=6.8Hz, 3H), 1.29(s,3H), 2.27(d, J=4.0Hz, 3H), 2.74(s, 3H), 3.03(q, J=6.8Hz, 1H), 6.45(d,J=8.0Hz, 1H), 6.94(d, J=1.6Hz, 1H), 7.05(dd, J=2.0, 8.0Hz, 1H), 9.30(d,J=19.6Hz, 1H).

Example 120 Methyl(E,E,E)-7-(1,2,3,4-tetramethyl-indolin-5-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoate##STR213##

In a similar manner to that described in Step 3 of Example 2, the titlecompound was prepared from(E)-3-(1,2,3,3-tetramethyl-indolin-5-yl)-2-fluoro-2-butenal prepared inPreparative Example 20.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.03(s, 3H), 1.20(d, J=6.4Hz, 3H), 1.28(s,3H), 2.14(d, J=3.6Hz, 3H), 2.18(d, J=1.2Hz, 3H), 2.73(s, 3H), 2.96(q,J=6.4Hz, 1H), 3.70(s, 3H), 5.84(s, 1H), 6.48(d, J=8.0Hz, 1H), 6.50(d,J=13.6Hz, 1H), 6.62(dd, J=16.0, 26.0Hz, 1H), 6.89(d, J=2.0Hz, 1H),7.00(dd, J=2.0, 8.0Hz, 1H).

Example 121(E,E,E)-7-(1,2,3,3-Tetramethyl-indolin-5-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoicacid ##STR214##

In a similar manner to that described in Step 4 of Example 2, the titlecompound was prepared from methyl(E,E,E)-7-(1,2,3,4-tetramethyl-indolin-5-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoateprepared in Example 120.

¹ H-NMR (400 MHz, CDCl₃) δ: 1.03(s, 3H), 1.20(d, J=6.4Hz, 3H), 1.29(s,3H), 2.15(bs, 3H), 2.19(s, 3H), 2.73(s, 3H), 2.92-3.00(m, 1H), 5.87(s,1H), 6.48(d, J=8.0Hz, 1H), 6.53(d, J=15.2Hz, 1H), 6.66(dd, J=15.6,26.0Hz, 1H), 6.89(bs, 1H), 7.00(bd, J=8.4Hz, 1H).

Preparative Example 21(E)-3-(2-Methoxy-6-isopropoxy-4-pyridyl)-2-butenal ##STR215##

2-Hydroxy-6-methoxy-4-carbomethoxy-pyridine was isopropylated into2-methoxy-6-isopropoxy-4-carbomethoxy-pyridine in a similar manner tothat described in Step 1 of Example 1. The pyridine derivative thusobtained was converted into an aldehyde in a similar manner to thatdescribed in Step 2 of Example 1. This aldehyde was treated in a similarmanner to that described in Steps 3 to 5 of Example 1 and Steps 1 and 2of Example 2 to give the title compound.

¹ H-NMR(CDCl₃, 400 MHz) δ: 1.36(d, J=6.2Hz, 6H), 2.48(s, 3H), 3.91(s,3H), 5.26(Hept., J=6.2Hz, 1H), 6.27-6.35(m, 3H), 10.14-10.19(m, 1H).

Example 122(E,E,E)-7-(2-Methoxy-6-isopropoxy-4-pyridyl)-3-methyl-octa-2,4,6-trienoic acid ##STR216##

In a similar manner to that described in Steps 3 and 4 of Example 2, thetitle compound was prepared from(E)-3-(2-methoxy-6-isopropoxy-4-pyridyl)-2-butenal prepared inPreparative Example 21.

¹ H-NMR(CDCl₃, 400 MHz) δ: 1.35(d, 6H, J=6.2Hz), 2.18(s, 3H), 2.38(s,3H), 3.90(s, 3H), 5.26(hept., J=6.21Hz, 1H), 5.86(s, 1H), 6.34(s, 2H),6.42(d, J=15.2Hz, 1H), 6.62-6.67(m, 1H), 7.01(dd, J=11.2, 15.2Hz, 1H).pale-yellow solid

Preparative Example 225,8-Dimethyl-2-(2-furyl)-5,6,7,8-tetrahydroquinoline ##STR217##

The title compound was prepared according to the method of F. Krohnke etal. (Synthesis, 1976, 1-24).

¹ H-NMR(400 MHz, CDCl₃) 1.27, 1.29(2xd, J=7.0Hz, 3H), 1.38, 1.40(2xd,J=7.0Hz, 3H), 1.43-1.76(m, 2H), 1.83-2.08(m, 2H), 2.85-3.04(m, 2H),6.49(s, 1H), 6.98(s, 1H), 7.40-7.51(m, 2H).

Preparative Example 235,8-Dimethyl-2-carbomethoxy-5,6,7,8-tetrahydroquinoline ##STR218##

5,8-Dimethyl-2-(2-furyl)-5,6,7,8-tetrahydroquinoline (3 g) was dissolvedin 100 ml of methanol. Ozone generated from oxygen at -78° C. wasintroduced into the obtained solution for 10 minutes. The resultingsystem was saturated with nitrogen gas, followed by the addition of 7 mlof dimethyl sulfide. The temperature of the mixture was raised to roomtemperature and the resulting reaction mixture was concentrated to giveabout 3 g of a crude product. This crude product containing a carboxylicacid was dissolved in 10 ml of DMF, followed by the addition of 1 ml ofmethyl iodide and 3.6 g of K₂ CO₃. The obtained mixture was stirred atroom temperature for one hour, followed by the addition of 30 ml ofwater. The obtained mixture was extracted with ethyl acetate (50 ml×2)and the organic phase was washed with a saturated aqueous solution ofcommon salt, dried over MgSO₄ and concentrated. The obtained mixture waspurified by column chromatography to give 1.6 g of the objectivecompound.

¹ H-NMR(400 MHz, CDCl₃) 1.28, 1.30(2xd, J=7.0Hz, 3H), 1.36, 1.40(2xd,J=7.0Hz, 3H), 1.42-1.79(m, 2H), 1.84-2.18(m, 2H), 2.91-3.16(m, 2H),3.97(s, 3H), 7.57, 7.59(2xd, J=7.5Hz, 1H), 7.88, 7.89(2xd, J=7.5Hz, 1H).

Preparative Example 245,8-Dimethyl-5,6,7,8-tetrahydroquinoline-2-carbaldehyde ##STR219##

In a similar manner to that described in Steps 1 and 2 of Example 2, thetitle compound was prepared from5,8-dimethyl-2-carbomethoxy-5,6,7,8-tetrahydroquinoline prepared inPreparative Example 23.

¹ H-NMR(400 MHz, CDCl₃) 1.31, 1.33(2xd, J=7.1Hz, 3H), 1.40, 1.44(2xd,J=7.1Hz, 3H), 1.45-1.79(m, 2H), 1.86-2.20(m, 2H), 2.94-3.12(m, 2H),7.64(d, J=7.9Hz, 1H), 7.73(d, J=7.9Hz, 1H).

Example 123 Ethyl(E)-3-(5,8-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-butenoate##STR220##

In a similar manner to that described in Steps 3 to 5 of Example 1, thetitle compound was prepared from5,8-dimethyl-5,6,7,8-tetrahydroquinoline-2-carbaldehyde prepared inPreparative Example 24.

¹ H-NMR(400 MHz, CDCl₃) 1.27, 1.28(2xd, J=7.6Hz, 3H), 1.32(t, J=7.0Hz,3H), 1.42-1.75(m, 2H), 1.83-2.16(m, 2H), 2.60(s, 3H), 2.88-3.01(m, 2H),4.22(q, J=7.0Hz, 2H), 6.74(s, 1H), 7.31(d, J=7.7Hz, 1H), 7.47, 7.49(2xd,J=7.7Hz, 1H).

Example 124 Methyl (E,E,E)-7-(5,8-dimethyl-5,6,7,8-tetrahydro-quinolin-2-3-methyl-octa-2,4,6-trienoate ##STR221##

In a similar manner to that described in Steps 1 to 3 of Example 2, thetitle compound was prepared from ethyl(E)-3-(5,8-dimethyl-5,6,7,8-tetrahydro-quinolin-2-yl)-2-butenoateprepared in Example 123.

¹ H-NMR(400 MHz, CDCl₃) 1.27, 1.28(2xd, J=6.8Hz, 3H), 1.39, 1.42(2xd,J=6.8Hz, 3H), 1.42-1.75(m, 2H), 1.84-2.15(m, 2H), 2.29(s, 3H), 2.39(s,3H), 2.86-3.01(m, 2H), 3.72(s, 3H), 5.83(s, 1H), 6.48(d, J=15.6Hz, 1H),7.08(dd, J=11.6, 15.0Hz, 1H), 7.21(d, J=11.6Hz, 1H), 7.25(d, J=8.0Hz,1H), 7.43, 7.45(2xd, J=8.0Hz, 1H).

Example 125(E,E,E)-7-(5,8-Dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)3-methyl-octa-2,4,6-trienoicacid ##STR222##

In a similar manner to that described in Step 4 of Example 2, the titlecompound was prepared from methyl(E,E,E)-7-(5,8-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)-3-methyl-octa-2,4,6-trienoateprepared in Example 124. ¹ H-NMR(400 MHz, CDCl₃) 1.27, 1.28(2xd,J=6.8Hz, 3H), 1.40, 1.43(2xd, J=6.8Hz, 3H), 1.44-1.76(m, 2H),1.84-2.16(m, 2H), 2.30(s, 3H), 2.40(s, 3H), 2.86-3.02(m, 2H), 5.86(1s,1H), 6.50(d, J=14.8Hz, 1H), 7.11(dd, J=11.6, 14.8Hz, 1H), 7.20-7.29(m,2H), 7.46(m, 1H).

Preparative Example 25 5-Carbethoxy-3-(2,6-dimethylphenyl)isoxazole##STR223##

4.66 g of hydroxylamine hydrochloride and 13 g of sodium acetate wereadded to 70 ml of a methanolic solution of 4.5 g of2,6-dimethylbenzaldehyde. The obtained mixture was heated at 60° C. for4 hours and distilled to remove the solvent. Water was added to theresidue, followed by the extraction with ethyl acetate. The organicphase was washed with a saturated aqueous solution of common salt, driedover magnesium sulfate and concentrated in a vacuum to give 4.8 g of acrude oxime having the following structure as a pale-yellow oil:##STR224##

¹ H-NMR(400 , CDCl₃) δ: 2.41(6H, s), 7.06(d, J=8.0Hz, 2H), 7.16(dd,J=8.0, 8.0Hz, 1H), 7.95(bs, 1H), 8.43(s, 1H). 3.77 g of ethyl propionateand 56 ml of a 6% aqueous solution of sodium hypochlorite were added to120 ml of 4.8 g of the above crude oxime in methylene chloride, followedby the stirring for one hour. The organic phase was washed with asaturated aqueous solution of sodium hydrogencarbonate, dried overmagnesium sulfate and concentrated in a vacuum. The residue was purifiedby silica gel column chromatography (5% ethyl acetate/hexane) to give6.9 g of the title compound as a pale-yellow oil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.10(t, J=6.0Hz, 3H), 2.14(s, 3H), 4.48(q,J=6.0Hz, 2H), 6.91(s, 1H), 7.10(d, J=7.6Hz, 1H), 7.12(d, J=7.6Hz, 1H),7.23(bs, 1H).

Preparative Example 26 3-(2,6-Dimethylphenyl)isoxazole-5-carbaldehyde##STR225##

In a similar manner to that described in Steps 1 and 2 of Example 2, thetitle compound was prepared from5-carbethoxy-3-(2,6-dimethylphenyl)isoxazole prepared in PreparativeExample 25.

¹ H-NMR(400 MHz, CDCl₃) δ: 2.28(6H, s), 6.96(1H, s), 7.15(d, J=8.4Hz,2H), 7.29(t, J=8.4Hz, 1H), 10.07(1H.sub., s).

Preparative Example 27 1-[3-(2,6-Dimethylphenyl)isoxazol-5-yl]-ethanone##STR226##

In a similar manner to that described in Steps 3 and 4 of Example 1, thetitle compound was prepared from3-(2,6-dimethylphenyl)isoxazole-5-carbaldehyde prepared in PreparativeExample 26.

¹ NMR(400 MHz, CDCl₃) δ: 2.18(s, 6H, 2.70(s, 3H), 6.88(d, J=0.8Hz, 1H),7.14(d, J=7.4Hz, 2H), 7.26(t, J=7.4Hz, 1H).

Preparative Example 28(E)-3-[3-(2,6-Dimethylphenyl)isoxazol-5-yl]-2-butenal ##STR227##

In a similar manner to that described in Step 5 of Example 1 and Steps 1and 2 of Example 2, the title compound was prepared from1-[3-(2,6-dimethylphenyl)-isoxazol-5-yl]-ethanone prepared inPreparative Example 27.

¹ H-NMR(400 MHz, CDCl₃) δ: 2.18(s, 6H), 2.57(s, 3H), 6.55(s, 1H),6.74(dd, J=7.6, 1.6Hz, 1H), 7.12(d, J=7.6Hz, 2H), 7.25(t, J=7.6Hz, 1H),10.22(d, 7.22(t,J=7.6Hz, 1H).

Example 126(E,E,E)-7-[3-(2,6-Dimethylphenyl)isoxazol-5-yl]-3-methyl-octa-2,4,6-trienoicacid ##STR228##

In a similar manner to that described in Steps 3 and 4 of Example 2, thetitle compound was prepared from(E)-3-[3-(2,6-dimethylphenyl)isoxazol-5-yl]-2-butenal prepared inPreparative Example 28.

¹ H-NMR(400 MHz, DMSO-d₆) δ: 2.10(s, 6H), 2.21(s, 3H), 2.32(s, 3H),5.88(br.s, 1H), 6.62-6.83(m, 2H), 7.04(d, J=9.6Hz, 1H), 7.14(d, J=7.2Hz,2H), 7.25(t, J=7.2Hz, 1H).

Preparative Example 29(Z)-3-[3-(2,6-Dimethylphenyl)isoxazol-5-yl]-2-fluoro-2-butenal##STR229##

In a similar manner to that described in Steps 1 and 2 of Example 6, thetitle compound was prepared from1-[3-(2,6-dimethylphenyl)isoxazol-5-yl]-ethanone prepared in PreparativeExample 27.

¹ H-NMR(400 MHz, CDCl₃) δ: 2.19(s, 6H), 2.62(d, J=4.0Hz, 3H), 6.82(d,J=3.6Hz, 1H), 7.13(d, J=8.0Hz, 2H), 7.26(t, J=8.0Hz, 1H), 9.96(d,J=18.0Hz, 1H).

Example 127(E,E,Z)-7-[3-(2,6-Dimethylphenyl)isoxazol-5-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid ##STR230##

In a similar manner to that described in Steps 3 and 4 of Example 2, thetitle compound was prepared from(Z)-3-[3-(2,6-dimethylphenyl)isoxazol-5-yl]-2-fluoro-2-butenal preparedin Preparative Example 29.

¹ H-NMR(400 MHz, DMSO-d₆) δ: 2.10(s, 6H), 2.23(s, 3H), 2.32(s, 3H),6.07(bs, 1H), 6.79-6.90(m, 2H), 7.02(d, J=16.4Hz, 1H), 7.15(d, J=7.2Hz,2H), 7.26(t, J=7.2Hz, 1H).

Preparative Example 30(E)-3-[3-(2,6-Dimethylphenyl)isoxazol-5-yl]-2-fluoro-2-butenal##STR231##

In a similar manner to that described in Steps 1 to 3 of Example 5, thetitle compound was prepared from1-[3-(2,6-dimethylphenyl)isoxazol-5-yl]-ethanone prepared in PreparativeExample 27.

¹ H-NMR(400 MHz, CDCl₃) δ: 2.20(s, 6H), 2.33(d, J=4.0Hz, 3H), 6.50(s,1H), 7.14(d, J=7.2Hz, 2H), 7.27(t, J=7.2Hz, 1H), 10.18(d, J=20Hz, 1H).

Example 128(E,E,E)-7-[3-(2,6-Dimethylphenyl)isoxazol-5-yl]-6-fluoro-3-methyl-octa-2,4,6-trienoicacid ##STR232##

In a similar manner to that described in Steps 3 and 4 of Example 2, thetitle compound was prepared from(E)-3-[3-(2,6-dimethylphenyl)isoxazol-5-yl]-2-fluoro-2-butenal preparedin Preparative Example 30.

¹ H-NMR(400 MHz, DMSO-d₆) δ: 2.14(s, 6H), 2.25(s, 3H), 2.48(s, 3H),6.08(s, 1H), 6.80-6.94(m, 3H), 7.15(s, 1H), 7.16(d, J=7.6Hz, 2H),7.20-7.29(m, 3H).

Preparative Example 31 5-Isopropyl-1-t-butylpyrazole-3-carbaldehyde##STR233## Step 1

6.3 g of metallic sodium was added to 100 ml of toluene. The obtainedmixture was vigorously stirred at 110° C. for 30 minutes to prepare adispersion of sodium in toluene. A liquid mixture comprising 26 g ofmethyl methoxyacetate and 39 g of 3-methyl-butyl-2-one was dropped intothe above dispersion with the bulk temperature being kept at 55 to 60°C. The obtained mixture was further stirred at 60° C. for 3 hours andcooled to 0° C., followed by the addition of 10 ml of ethanol and 50 mlof 10% hydrochloric acid. The obtained mixture was extracted with ethylacetate. The organic phase was washed with a saturated aqueous solutionof common salt, dried over magnesium sulfate and concentrated in avacuum to give 40 g of a crude diketone having the following structure:##STR234##

¹ H-NMR(400 MHz, CDCl₃) δ: 1.16(d, J=6.0Hz, 6H), 3.43(s, 3H), 4.00(s,2H), 5.80(s, 1H).

Step 2

9.46 g of t-butylhydrazine hydrochloride was added to 100 ml of anethanolic solution of 10 g of the above diketone. The obtained mixturewas heated under reflux for 2 hours and distilled to remove the solvent.Water was added to the residue, followed by the extraction with ethylacetate. The organic phase was washed with a saturated aqueous solutionof common salt, dried over magnesium sulfate and concentrated in avacuum to give 8.1 g of a pyrazole having the following structure as apale-yellow oil: ##STR235##

¹ H-NMR(400 MHz, CDCl₃) δ: 1.24(d, J=6.0Hz, 6H), 1.62(s, 9H),3.28-3.36(m, 1H), 3.40(s, 3H), 4.28(s, 2H), 6.14(s, 1H).

Step 3

42.3 ml of a 1.0M solution of boron tribromide in methylene chloride wasdropped into 230 ml of a solution of 8.1 g of the above pyrazole inmethylene chloride at 0C. After the completion of the dropping, theobtained mixture was further stirred at 0° C. for 30 minutes and pouredinto 200 ml of 10% aqueous ammonia, followed by the extraction withethyl acetate. The organic phase was washed with a saturated aqueoussolution of common salt, dried over magnesium sulfate and concentratedin a vacuum to give 9.3 g of a crude bromide.

Water (90 ml) and sodium carbonate (7.3 g) were added to 90 ml of asolution of 9.3 g of the above bromide in 1,4-dioxane. The obtainedmixture was heated under reflux for 1.5 hours and distilled to removethe 1,4-dioxane, followed by the extraction with ethyl acetate. Theorganic phase was washed with a saturated aqueous solution of commonsalt, dried over magnesium sulfate and concentrated in a vacuum to give6.7 g of a crude alcohol as a yellow oil.

Manganese dioxide (35 g) was added to 150 ml of a solution of 6.7 g ofthe crude alcohol in methylene chloride. The obtained mixture wasstirred at room temperature for 15 hours and filtered through Celite.The filtrate was distilled to remove the solvent. The obtained residuewas purified by silica gel column chromatography (5% ethylacetate/hexane) to give 4.7 g of the title compound as a pale-yellowoil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.28(d, J=6.0Hz, 6H), 1.68(s, 9H),3.32-3.40(m, 1H), 6.66(s, 1H), 9.88(s, 1H).

Preparative Example 32 1-(5-Isopropyl-1-t-butylpyrazol-3-yl)ethanone##STR236##

In a similar manner to that described in Steps 3 and 4 of Example 1, thetitle compound was prepared from5-isopropyl-1-t-butylpyrazole-3-carbaldehyde prepared in PreparativeExample 31.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.26(d, J=6.0Hz, 6H), 1.66(s, 9H), 2.52 (s,3H), 3.32-3.40(m, 1H), 6.44(s, 1H).

Preparative Example 33(E)-3-(5-Isopropyl-1-t-butylpyrazol-3-yl)-2-butenal ##STR237##

In a similar manner to that described in Step 5 of Example 1 and Steps 1and 2 of Example 2, the title compound was prepared from1-(5-isopropyl-1-t-butylpyrazol-3-yl)ethanone prepared in PreparativeExample 32.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.26(d, J=6.0Hz, 6H), 1.66(s, 9H), 2.54(d,J=1.2Hz, 3H), 3.32-3.40(m, 1H), 6.43(s, 1H), 6.52(dd, J=1.2, 8.4Hz, 1H),10.16(d, J=8.4Hz, 1H).

Example 129(E,E,E)-7-(5-Isopropyl-1-t-butylpyrazol-3-yl)-3-methyl-octa-2,4,6-trienoicacid ##STR238##

In a similar manner to that described in Steps 3 and 4 of Example 2, thetitle compound was prepared from(E)-3-(5-isopropyl-1-t-butylpyrazol-3-yl)-2-butenal prepared inPreparative Example 33.

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.21(d, J=6.8Hz, 6H), 1.57(s, 9H), 2.13(s,3H), 2.27(s, 3H), 5.75(s, 1H), 6.41(d, J=15.2Hz, 1H), 6.47(s, 1H),6.71(d, J=11.6Hz, 1H), 7.02(dd, J=11.6, 15.2Hz, 1H).

Preparative Example 34(E)-2-Fluoro-3-(5-isopropyl-1-t-butylpyrazol-3-yl)-2-butenal ##STR239##

In a similar manner to that described in Steps 1 to 3 of Example 5, thetitle compound was prepared from1-(5-isopropyl-1-t-butylpyrazol-3-yl)ethanone prepared in PreparativeExample 32.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.29(d, J=7.2Hz, 6H), 1.64(s, 9H), 2.22(d,J=4.0Hz, 3H), 3.32-3.40(m, 1H), 6.28(s, 1H), 10.08(d, J=20Hz, 1H).

Example 130(E,E,E)-6-Fluoro-7-(5-isopropyl-1-t-butylpyrazol-3-yl)-3-methyl-octa-2,4,6-trienoicacid ##STR240##

In a similar manner to that described in Steps 3 and 4 of Example 2, thetitle compound was prepared from(E)-2-fluoro-3-(5-isopropyl-1-t-butylpyrazol-3-yl)-2-butenal prepared inPreparative Example 34.

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.22(d, J=6.8Hz, 6H), 1.60(s, 9H), 2.04(s,3H), 2.22(s, 3H), 3.32-3.42(m, 1H), 5.92(s, 1H), 6.41(s, 1H), 6.58(d,J=16.0Hz, 1H), 7.82(dd, J=16.0, 30.0Hz, 1H).

Preparative Example 351-(2,5-Dimethylphenyl)-5-methylpyrazole-3-carbaldehyde ##STR241##

The title compound was prepared in a similar manner to that described inPreparative Example 31.

¹ H-NMR(400 MHz, CDCl₃) δ: 2.02(s, 3H), 2.14(s, 3H), 2.18(s, 3H),6.71(s, 1H), 7.08(s, 1H), 7.24(br.s, 2H).

Preparative Example 36(E)-3-[1-(2,5-Dimethylphenyl)-5-methylpyrazol-3-yl]-2-butenal ##STR242##

In a similar manner to that described in Steps 2 to 5 of Example 1 andSteps 1 and 2 of Example 2, the title compound was prepared from1-(2,5-dimethyl-phenyl)-5-methylpyrazole-3-carbaldehyde prepared inPreparative Example 35.

¹ H-NMR(400 MHz, CDCl₃) δ: 2.02(s, 3H), 2.14(s, 3H), 2.36(s, 3H),2.58(d, J=1.2Hz, 1H), 6.48(s, 1H), 6.54(dd, J=1.2, 8.0Hz, 1H), 7.06(s,1H), 7.18(d, J=8.0Hz, 1H), 7.21(d, J=8.0Hz, 1H), 10.20(d, J=8.0Hz, 1H).

Example 131 (E,E,E)-7-[1-(2,5-Dimethylphenyl)-5-methylpyrazol-3-yl]-3-methyl-octa-2,4,6-trienoic acid ##STR243##

In a similar manner to that described in Steps 3 and 4 of Example 2, thetitle compound was prepared from(E)-3-[1-(2,5-dimethylphenyl)-5-methylpyrazol-3-yl]-2-butenal preparedin Preparative Example 36.

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.91(s, 3H), 2.03(s, 3H), 2.15(s, 3H),2.28(s, 3H), 2.48(s, 3H), 5.78(s, 1H), 6.47(d, J=15.2Hz, 1H), 6.52(s,1H), 6.81(d, J=11.6Hz, 1H), 7.07(dd, J=11.6, 15.2Hz, 1H), 7.09(s, 1H),7.21(d, J=8Hz, 1H), 7.26(d, J=8Hz, 1H).

Preparative Example 375-Isopropyl-1-(2,2,2-trifluoroethyl)pyrazole-3-carbaldehyde ##STR244##

The title compound was prepared in a similar manner to that described inPreparative Example 31.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.28(d, J=6.0Hz, 6H), 2.92-3.04(m, 1H),4.76(dd, J=8.0, 16.4Hz, 2H), 6.66(1H, s), 9.94(s, 1H).

Preparative Example 381-[5-Isopropyl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]ethanone ##STR245##

In a similar manner to that described in Steps 3 and 4 of Example 1, thetitle compound was prepared from5-isopropyl-1-(2,2,2-trifluoroethyl)pyrazole-3-carbaldehyde prepared inPreparative Example 37.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.28(d, J=6Hz, 6H), 2.54(s, 3H), 2.90-3.00(m,1H), 4.71(dd, J=8.0, 16.4Hz, 2H), 6.63(s, 1H).

Preparative Example 39(E)-3-[5-Isopropyl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]-2-butenal##STR246##

In a similar manner to that described in Step 5 of Example 1 and Steps 1and 2 of Example 2, the title compound was prepared from1-[5-isopropyl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]ethanone prepared inPreparative Example 38.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.28(d, J=6Hz, 6H), 2.54(s, 3H), 2.90-3.00(m,1H), 4.67(dd, J=8.0, 16.4Hz, 2H), 6.39(s, 1H), 6.50(dd, J=1.6, 8.0Hz,2H), 10.20(d, J=8.0Hz, 1H).

Example 132(E,E,E)-7-[5-Isopropyl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]-3-methyl-octa-2,4,6-trienoicacid ##STR247##

In a similar manner to that described in Steps 3 and 4 of Example 2, thetitle compound was prepared from(E)-3-[5-isopropyl-1-(2,2,2-trifluoroethyl)-pyrazol-3-yl]-2-butenalprepared in Preparative Example 39.

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.28(d, J=6Hz, 6H), 2.12(s, 3H), 2.28(s,3H), 3.00-3.12(m, 1H), 5.05(dd, J=8.0, 16.4Hz, 2H), 5.78(s, 1H), 6.33(s,1H), 6.47(d, J=15.2Hz, 1H), 6.80(d, J=10.8Hz, 1H), 7.03(dd, J=10.8,15.2Hz, 1H).

Pharmacological Experimental Examples will be described to illustratethe effects of the present invention.

Receptor binding assay using nuclear extract fraction of cells bearingRXR a genes transferred thereto

A human RXR α gene was transferred into BHK (baby hamster kidney) cellsto prepare cells constantly expressing RXR α proteins. The specificbinding of 9-cis retinoic acid for RXR was determined by the use of anuclear extract fraction of the cells, and the ability of each compoundto bind RXR was determined by measuring the inhibition against thespecific binding.

The nuclear extract fraction was prepared as follows.

The above BHK cells (5×10⁹) into which an RXR α gene had beentransferred were suspended in 15 ml of solution A (sodium phosphate(pH7.4): 5 mM, monothioglycerol: 10 mM, glycerol: 10% (v/v),phenylmethylsulfonyl fluoride (PMSF): 1 mM, aprotinin: 10 μg/ml, andleupeptin: 25 μ g/ml). The obtained suspension was homogenized by theuse of a homogenizer and centrifuged to remove the resultingsupernatant. The sediment thus formed was suspended in 15 ml of solutionB (Tris-HCl (pH8.5): 10 mM, monothioglycerol: 10 mM, glycerol: 10%(v/v), PMSF: 1 mM, aprotinin: 10 μg/ml, leupeptin: 25 μg/ml, and KCl:0.4M). The obtained suspension was allowed to stand at 4° C. for one hour,and subjected to ultracentrifugation (100,000 x g, 4° C., 1 hr). Theobtained supernatant was stored as the nuclear extract fraction in afrozen state at -80° C. until the use (METHODS IN ENZYMOLOGY, 189, 248).

The receptor binding assay was conducted as follows.

180 μl of the above fraction and 10 μl of a dilution of 9-cis retinoicacid or a test compound were added to each well of a 96-well plate madeof polypropylene, followed by the addition of 10 μl of 10 nM ³ H-9-cisretinoic acid. The resulting plate was allowed to stand at 4° C. for 16hours. A solution containing 3% of charcoal and 0.3% of dextran wasadded to the resulting reaction mixture. The mixture thus obtained wascentrifuged to remove free ³ H-9-cis retinoic acid. The radioactivity ofthe resulting supernatant was determined by the use of a scintillationcounter. The specific binding of ³ H-9-cis retinoic acid for RXR wasdetermined by assuming the radioactivity found when 200 times as much9-cis retinoic acid was added to be the non-specific binding andsubtracting it from the radioactivity determined above. The compounds ofthe present invention inhibited the binding of ³ H-9-cis retinoic aciddependently on the concentration. The 50% inhibitory concentration ofeach test compound was calculated and the relative activities werecalculated by assuming the inhibitory concentration of 9-cis retinoicacid to be 1.0. The results are given in Table 1.

                  TABLE 10                                                        ______________________________________                                                      Results of RXR α binding assay                              Ex. No. (relative IC.sub.50)                                                ______________________________________                                        control       1.0                                                               (9-cis Retinoic Acid)                                                         2 15.8                                                                        5 4.7                                                                         6 7.1                                                                         9 1.3                                                                         12 1.8                                                                        15 1.8                                                                        18 5.6                                                                        21 0.8                                                                        36 1.5                                                                        42 1.1                                                                        45 1.7                                                                        54 1.7                                                                        57 14.0                                                                       60 3.0                                                                      ______________________________________                                    

Method for experiment on RXR α transcription system

The method for determining the activity of novel retioid compounds ofaccelerating transcription through retinoid X receptor α (RXR α) willnow be described.

Human RXR α expression vectors and PLAP vectors (i.e., vectorscontaining integrated thereinto a secretor alkaline phosphatase (PLAP)gene of which the expression is inhibited by the competent sequence ofthe RXR α in the presence of a ligand were temporarily transferred intoCOS-7 (African green monkey kidney cells) and the PLAP activity wasdetermined by the chemiluminescence method. This PLAP gene is anartificial mutant deficient in membrane-binding site, so that it issecreted into a cell-culturing medium when expressed.

COS-7 cells (1.0×10⁶) were scattered on a 60-mm culture dish. One dayafter, human RXR α expression vectors and PLAP vectors were transferredinto the cells each in an amount of 10 ∞g by the DEAE-dextran method.Another day after, the resulting cells were torn off by trypsinizationand put on a 96-well culture plate in an amount of 2×10⁴ per unit well.Four hours after, the cells were put on 100 μl of a medium containingretinoid compounds in a concentration of 0 to 1 μM. Sampling wasconducted after 44 hours and the obtained samples were treated at 65° C.for 10 minutes to eliminate the non-specific activity. Sumilight (aproduct of Sumitomo Metal Industries, Ltd.) was used as the substrate ofthe chemiluminescence reaction. 30 minutes after the initiation of thereaction, the intensity of luminescence was determined. The results aregiven in FIG. 1. The plots are each given in terms of the average offive samples.

It is apparent from the above results that the compounds of the presentinvention exhibit agonism for RXR receptors. Therefore, the compoundsare expected to be useful as preventive and therapeutic agents forautoimmune diseases, immunosuppression in organ transplantation ormalignant neoplasm to give drugs efficacious against the followingvarious diseases:

various cornification anomalies, psoriasis, acne, leukoplakia, andxeroderma pigmentosum;

various alopeciae such as alopecia areata, seborrheic alopecia andcachectic alopecia;

postmenopausal osteoporosis, senile osteoporosis, idiopathicosteoporosis, diabetic osteopenia, rheumatoid osteopenia, renalosteomalacia and ectopic hyperostosis;

osteoarthritis and shoulder periarthritis;

rheumatoid arthritis, multiple sclerosis (MS), systemic lupuserythematosus (SLE), Behcet disease, mycosis fungoides (MF), systemicscleroderma, dermatomyositis (OM), nodular arteriosclerosis (PM),thrombocytopenia and insulin dependent diabetes melitus;

immunosuppression in organ transplantation;

atopic dermatitis and asthma;

hyperthyroidism;

squamous cell carcinoma, bladder cancer, lung cancer, esophagealcarcinoma, head and neck cancer, acute promyelocytic leukemia andmyelocytic leukemia;

hyperkalemia; and

pulmonary fibrosis, hepatic fibrosis, and hepatic cirrhosis.

The compounds of the present invention may be orally administered aspreventive or therapeutic agents for these diseases in the form oftablet, powder, granule, capsule, syrup or the like, or may beparenterally administered in the form of suppository, injection,external preparation or drop.

Pharmaceutical preparations for oral or parenteral administrationaccording to the present invention can be formulated by the use ofconventional pharmaceutically acceptable carriers in a conventionalmanner.

Subcutaneous, intramuscular or intravenous injections or droppinginjections according to the present invention can be formulated byconventional processes of adding a pH regulator, buffer, stabilizer orsolubilizing agent to a base at need and, if necessary, freeze-dryingthe obtained mixture.

The compounds according to the second embodiment of the presentinvention and the preparation thereof will now be described in moredetail by referring to the following Examples, though the presentinvention is not limited by them. Further, the preparation of startingcompounds used in the Examples will be described in ReferentialExamples. No peak assignable to carboxyl was detected in NMRspectroscopy of some compounds. The determination of melting points wasconducted by the use of a melting point apparatus for trace samples(mfd. by Yanagimoto Manufacturing Co., Ltd.)

Example 201 Preparation of4-[5,6-dihydro-2,3-diisopropyl-9-(3-pyridylmethyl)pyrrolo[2,3-f]auinoxalin-7-yl]benzoicacid

Step 1

Preparation of methyl4-(7,8-dihydro-2,3-diisopropyl-5(2H)-quinoxalinon-6-ylidene)benzoate##STR248##

2.0 g of 5,6,7,8-tetrahydro-2,3-didiisopropyl-5-quinoxalinone and 1.27 gof methyl terephthal-aldehydate were dissolved in 10 ml of acetic acid,followed by the addition of 2 ml of concentrated sulfuric acid. Theobtained mixture was stirred at room temperature overnight and pouredinto a saturated aqueous solution of sodium hydrogencarbonate. Theobtained mixture was extracted with ethyl acetate. The organic phase waswashed with water and a saturated aqueous solution of common salt, driedover anhydrous magnesium sulfate and concentrated in a vacuum. Theresidue was purified by silica gel column chromatography (developer: 20%ethyl acetate/hexane) to give 1.04 g of the title compound as a whitesolid. M.p.: 100 to 102° C.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.31(d, J=6.8Hz, 6H), 1.37(d, J=6.8Hz, 6H),3.10-3.22(m, 4H), 3.38-3.47(m, 2H), 3.05(s, 3H), 7.50(d, J=8.2Hz, 2H),7.89(s, 1H), 8.09(d, J=8.2Hz, 2H).

Step 2

Preparation of methyl 4-[1-(7,8-dihydro-2,3-diisopropyl-5 (2H)-quinoxalinon-6-yl) -2,2-dimethoxyethyl]benzoate ##STR249##

1.0 g of methyl4-(7,8-dihydro-2,3-diisopropyl-5(2H)-quinoxalinon-6-ylidene)benzoate wasdissolved in a solvent mixture comprising 12 ml of nitromethane and 4 mlof tetrahydrofuran, followed by the addition of 1 ml of a 40% methanolicsolution of benzyltrimethyl-ammonium hydroxide. The obtained mixture wasstirred at room temperature overnight, followed by the addition of ethylacetate. The organic phase was washed with dilute hydrochloric acid,water, a saturated aqueous solution of sodium hydrogencarbonate and asaturated aqueous solution of common salt successively, dried overanhydrous magnesium sulfate and concentrated in a vacuum to give 1.38 gof a brown oil.

This oil was dissolved in a solvent mixture comprising 15 ml ofmethylene chloride and 15 ml of tetrahydrofuran. 1.5 ml of a 28%solution of sodium methoxide was added to the solution at -35° C.,followed by the stirring for 40 minutes.

This solution was dropped into a separately prepared solvent mixturecomprising 4 ml of concentrated sulfuric acid and 20 ml of methanol at-35° C. The obtained mixture was stirred at room temperature for 30minutes and poured into a saturated aqueous solution of sodiumhydrogencarbonate. The obtained mixture was extracted with ethylacetate. The organic phase was washed with water and a saturated aqueoussolution of common salt, dried over anhydrous magnesium sulfate andconcentrated in a vacuum to give 1.24 g of the title compound as a brownpowder. This powder was used in the subsequent step without furtherpurification.

Step 3

Preparation of 4-[5,6-dihydro-2,3-diisopropyl-9-(3-pyridylmethyl)pyrrolo[2,3-f]quinoxalin-7-yl]benzoic acid ##STR250##

0.6 g of methyl4-[1-(7,8-dihydro-2,3-diisopropyl-5(2H)-quinoxalinon-6-yl)-2,2-dimethoxyethyl]benzoateand 0.202 ml of 3-aminomethylpyridine were dissolved in 10 ml of aceticacid. The obtained solution was heated under reflux for one hour andcooled to room temperature by allowing to stand, followed by theaddition of water. The obtained mixture was extracted with ethylacetate. The organic phase was washed with a saturated aqueous solutionof sodium hydrogen-carbonate and a saturated aqueous solution of commonsalt, dried over anhydrous magnesium sulfate, and concentrated in avacuum. The obtained residue was purified by silica gel chromatography(developer: 30% ethyl acetate/hexane) to give 0.15 g of a light-brownpowder.

This powder was dissolved in 15 ml of ethanol, followed by the additionof 5 ml of a 5N aqueous solution of sodium hydroxide. The obtainedmixture was stirred at room temperature for 4 hours. Dilute hydrochloricacid was added to the mixture under stirring to precipitate crystals.The crystals were recovered by filtration, washed with water and driedin a vacuum to give 0.1 g of the title compound as a light-brown solid.

M.p.: 158 to 160° C.

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.01(d, J=6.6Hz, 6H), 1.17(d, J=6.6Hz, 6H),3.04(s, 4H), 3.18-3.32(m, 2H), 5.90(s, 2H), 7.30(dd, J=4.6, 7.8Hz, 1H),7.44(d, J=7.8Hz, 1H), 7.52(d, J=7.9Hz, 2H), 7.54(s, 1H), 7.91(d,J=7.9Hz, 2H), 8.38(s, 1H), 8.41(d, J=4.6Hz, 1H).

The compound of Example 202 was prepared in a similar manner to thatdescribed in Example 201.

Example 203

Preparation of4-[4,5-dihydro-7,8-diisopropyl-1-(3-pyridylmethyl)pyrazolo[5,4-f]quinoxalin-3-yl]benzoicacid

Step 1

Preparation of methyl 4-(7,8-dihydro-2,3-diisopropyl-5(2H)-quinoxalinon-6-yl-carbonyl)benzoate ##STR251##

0.74 g of 5,6,7,8-tetrahydro-2,3-diisopropyl-5-quinoxaline was dissolvedin 20 ml of tetrahydrofuran. 3.51 ml of a 1M tetrahydrofuran solution oflithium bistrimethylsilylamide was dropped into the solution at -78° C.The obtained mixture was stirred for 30 minutes, followed by theaddition of a solution of 0.7 g of chloride of monomethyl terephthalatein 5 ml of tetrahydrofuran. The obtained mixture was stirred for onehour, followed by the addition of a saturated aqueous solution ofammonium chloride. The obtained mixture was extracted with ethylacetate. The organic phase was washed with water and a saturated aqueoussolution of common salt, dried over anhydrous magnesium sulfate andconcentrated in a vacuum. The residue was purified by silica gelchromatography (developer: 10% ethyl acetate/hexane) to give 0.58 g ofthe title compound as a brown solid. M.p.: 82 to 84° C.

¹ HNM(400 MHz, CDCl₃) δ: 1.30(d, J=6.8Hz, 6H), 1.36(d, J=6.8Hz, 6H),2.82-2.87(m, 2H), 3.00-3.04(m, 2H), 3.37-3.45(m, 2H), 3.96(s, 3H),7.66(d, J=8.6Hz, 2H), 8.14(d, J=8.6Hz, 2H).

Step 2

Preparation of methyl4-(4,5-dihydro-7,8-diisopropylpyrazolo[5,4-f]quinoxalin-3-yl)benzoate##STR252##

0.58 g of methyl4-(7,8-dihydro-2,3-diisopropyl-5(2H)-quinoxaline-6-carbonyl)benzoate wasdissolved in 10 ml of acetic acid, followed by the addition of 0.107 mlof hydrazine monohydrate. The obtained mixture was heated under refluxfor 4 hours, cooled to room temperature by allowing to stand and, pouredinto a saturated aqueous solution of sodium hydrogen-carbonate. Theobtained mixture was extracted with ethyl acetate. The organic phase waswashed with water and a saturated aqueous solution of common salt, driedover anhydrous magnesium sulfate and concentrated in a vacuum. Theobtained residue was purified by silica gel chromatography (developer:5% ethyl acetate/hexane) to give 0.524 g of the title compound as apale-yellow solid.

M.p.: 204 to 206° C.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.30(d, J=6.8Hz, 6H), 1.32(d, J=6.8Hz, 6H),3.16-3.26(m, 4H), 3.32-3.39(m, 2H), 3.95(s, 3H), 7.83(d, J=8.6Hz, 2H),8.12(d, J=8.6Hz, 2H).

Step 3

Preparation of4-[4,5-dihydro-7,8-diisopropyl-1-(3-pyridylmethyl)pyrazolo[54-f]quinoxalin-3-yl]benzoic acid ##STR253##

0.19 g of methyl4-(4,5-dihydro-7,8-diisopropyl-pyrazolo[5,4-f]quinoxalin-3-yl)benzoatewas dissolved in 10 ml of N,N-dimethylformamide. The obtained solutionwas cooled to 0° C., followed by the addition of 0.04 g of sodiumhydride. The obtained mixture was stirred for 10 minutes, followed bythe addition of 0.08 g of 3-picolyl chloride hydrochloride. The obtainedmixture was stirred for 10 minutes, then at room temperature for 30minutes, followed by the addition of a saturated aqueous solution ofammonium chloride. The precipitated crystals were recovered byfiltration, washed with water and dried in a vacuum to give 0.144 g of alight-brown powder.

This powder was dissolved in 15 ml of ethanol, followed by the additionof 5 ml of a 5N aqueous solution of sodium hydroxide. The obtainedmixture was stirred at room temperature for one hour, followed by theaddition of dilute hydrochloric acid under stirring. The crystals thusprecipitated were recovered by filtration, washed with water and driedin a vacuum to give 0.13 g of the title compound as a white solid.

M.p.: 279 to 281° C.

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.21(d, J=6.4Hz, 6H), 1.29(d, J=6.4Hz, 6H),3.14-3.25(m, 4H), 3.27-3.37(m, 2H), 6.16(s, 2H), 7.21-7.28(m, 1H),7.60-7.65(m, 1H), 7.85(d, J=8.2Hz, 2H), 8.17(d, J=8.2Hz, 2H),8.49-8.56(m, 1H), 8.58-8.66(m, 1H).

The compound of Example 204 was prepared in a similar manner to thatdescribed in Example 203.

    __________________________________________________________________________       Structural                                                                   Ex. Formula .sup.1 H-NMR (400 MHz, DMSO-d.sub.6) δ m.p. (°                                                 C.)                               __________________________________________________________________________      204                                                                                                                       1.01 (d, J                                                                  =6.8Hz, 6H), , 1.26 (d,                                                       J=6.8Hz, 6H), , 3.16˜3.3                                                1 (m, 7H) , 6.23 (s, 2H), ,                                                   6.75 (d, J=8.0Hz, 1H), ,                                                      7.12˜7.17 (m, 1H) ,                                                     7.54 (ddd, J=2.1, 8.0, 8.0Hz,                                                 1H), , 7.88 (d, J=8.6Hz, 2H),                                                 , 8.16 (d, J=8.6Hz, 2H), ,                                                    8.59˜8.63 (m, 1H).                                                      256˜258                     __________________________________________________________________________

Example 205 Preparation of4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)pyrrolo[2,3-a]phenazin-3-yl]benzoicacid

Step 1

Preparation of methyl4-[(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1(2H)-phenazinon-2-yl)hydroxymethyl]benzoate##STR255##

0.5 g of 1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetra-methylphenazin-1-oneand 0.38 g of methyl terephthal-aldehydate were dissolved in 15 ml ofmethanol, followed by the addition of a small amount of sodiumhydroxide. The obtained mixture was stirred overnight to precipitatecrystals. The crystals were recovered by filtration, washed with a smallamount of methanol and dried in a vacuum to give 0.53 g of the titlecompound as a white solid.

M.p.: 190 to 192° C.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.30(s, 3H), 1.32(s, 3H), 1.38(s, 6H),1.82(s, 4H), 1.85-1.92(m, 1H), 2.12-2.23(m, 1H), 2.89-2.92(m, 1H),2.93-3.16(m, 3H), 3.92(s, 3H), 5.78-5.81(m, 1H), 7.48(d, J=8.0Hz, 2H),8.06(d, J=8.0Hz, 2H).

Step 2

Preparation of methyl4-(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1(2H)-phenazinon-2-ylidene)benzoate##STR256##

0.53 g of methyl4-[(3,4,6,7,8,9-hexamethyl-6,6,9,9-tetramethyl-1(2H)-phenazinon-2-yl)hydroxy-methyl]benzoatewas dissolved in 12 ml of 1,4-dioxane, followed by the addition of 1 mlof concentrated sulfuric acid. The obtained mixture was stirred at 60°C. for 6 hours and poured into a saturated aqueous solution of sodiumhydrogencarbonate. The obtained mixture was extracted with ethylacetate. The organic phase was washed with a saturated aqueous solutionof common salt, dried over anhydrous magnesium sulfate and concentratedin a vacuum. The residue was washed with hexane, followed by therecovery of crystals by filtration. The crystals were dried in a vacuumto give 0.36 g of the title compound as a pale-yellow solid.

M.p.: 149 to 151° C.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.35(s, 6H), 1.41(s, 6H), 1.84(s, 4H),3.10-3.23(m, 2H), 3.95(s, 3H), 7.50(d, J=8.3Hz, 2H), 3.09(d, J=8.4Hz,2H).

Step 3

Preparation of methyl4-[1-(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1(2H)-phenazinon-2-yl)-2,2-dimethoxyethyl)benzoate##STR257##

0.6 g of methyl4-(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1(2H)-phenazinon-2-ylidene)benzoatewas dissolved in a solvent mixture comprising 7 ml of nitromethane and 3ml of tetrahydrofuran, followed by the addition of 0.3 ml of a 40%methanolic solution of benzyltrimethylammonium hydroxide. The obtainedmixture was stirred at room temperature overnight, followed by theaddition of ethyl acetate. The formed organic phase was washed withdilute hydrochloric acid, water, a saturated aqueous solution of sodiumhydrogencarbonate and a saturated aqueous solution of common saltsuccessively, dried over anhydrous magnesium sulfate, and concentratedin a vacuum to give 0.74 g of a light-brown oil.

This oil was dissolved in a solvent mixture comprising 15 ml ofmethylene chloride and 15 ml of tetrahydrofuran. 0.78 ml of a 28%solution of sodium methoxide was added to the solution at -35° C.,followed by the stirring for 40 minutes.

This solution was dropped into a separately prepared solvent mixturecomprising 2 ml of concentrated sulfuric acid and 10 ml of methanol at-35° C. The mixture was stirred at room temperature for 30 minutes andpoured into a saturated aqueous solution of sodium hydrogencarbonate,followed by the extraction with ethyl acetate. The organic phase waswashed with water and a saturated aqueous solution of common salt, driedover anhydrous magnesium sulfate and concentrated in a vacuum to give0.7 g of the title compound as a brown powder. This powder was used inthe subsequent step without further purification.

Step 4

Preparation of methyl4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)-pyrrolo[2,3-a]phenazin-3-yl]benzoate##STR258##

0.4 g of methyl4-[1-(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1(2H)-phenazinon-2-yl)-2,2-dimethoxyethyl]benzoateand 0.13 ml of 3-aminomethylpyridine were dissolved in 8 ml of aceticacid. The obtained solution was heated under reflux for one hour andcooled to room temperature by allowing to stand, followed by theaddition of water. The obtained mixture was extracted with ethylacetate. The organic phase was washed with a saturated aqueous solutionof sodium hydrogencarbonate and a saturated aqueous solution of commonsalt, dried over anhydrous magnesium sulfate and concentrated in avacuum. The obtained residue was purified by silica gel chromatography(developer: 30% ethyl acetate/hexane) to give 0.2 g of a brown powder.

This powder was dissolved in 15 ml of ethanol, followed by the additionof 5 ml of a 5N aqueous solution of sodium hydroxide. The obtainedmixture was heated at 60° C. for one hour and cooled to room temperatureby allowing to stand, followed by the addition of dilute hydrochloricacid under stirring. The crystals thus precipitated were recovered byfiltration, washed with water and dried in a vacuum to give 0.1 g of thetitle compound as a pale-yellow solid.

M.p.: 245 to 247° C.

¹ H-N.(400 MHz, DMSO-d₆) δ: 1.03(s, 6H), 1.23(s, 6H), 1.67(s, 4H),3.05(s, 4H), 5.89(s, 2H), 7.28-7.33(m, 1H), 7.40-7.44(m, 1H), 7.55(d,J=8.0Hz, 2H), 7.57(s, 1H), 7.92(d, J=8.0Hz, 2H), 8.34-8.37(m, 1H),8.38-8.43(m, 1H).

In a similar manner to that described in Example 205, the compounds ofExamples 206 to 212 were prepared by the use of the ketones prepared inReferential Examples 2 and 3 and6,7,8,9-tetrahydro-9,9-dimethylothianaphtho[2,3-b]cyclohexan-1-oneprepared in a similar manner to that described in Referential Example 3.

    __________________________________________________________________________       Structural                                                                   Ex. Formula .sup.1 H-NMR (400 MHz, DMSO-d.sub.6) δ m.p. (°                                                  C.)                              __________________________________________________________________________      206                                                                                                                        0.93 (s, 6H), 1.21 (s,                                                      6H),  1.64 (s, 4H), 3.05 (s,                                                  4H),  5.85 (s, 2H),                                                           ˜7.00 (m, 2H),                                                          7.53˜7.56 (m, 3H),                                                      7.94 (d, J=8.4Hz, 2H),                                                        8.42˜8.48 (m, 2H).                                                      238˜240                       - 207                                                                                                                     0.89 (s, 6H), 1.20 (s,                                                      6H),  1.62 (s, 4H),                                                           3.01˜3.11 (m, 4H),                                                      5.88 (s, 2H),  6.65 (d,                                                       J=7.7Hz, 1H),  7.18˜7.2                                                 2 (m, 1H),  7.56 (s, 1H),                                                     7.57 (d, J=8.2Hz, 2H),                                                        7.62˜7.65 (m, 1H),                                                      7.94 (d, J=8.2Hz, 2H),                                                        8.50˜8.52 (m, 1H).                                                      282˜284                       - 208                                                                                                                     1.06 (s, 6H), 1.23 (s,                                                      6H),  1.67 (s, 4H), 3.04 (s,                                                  4H),  7.06˜7.11 (m,                                                     2H),  7.16˜7.21 (m,                                                     1H),  7.24˜7.30 (m,                                                     2H),  7.51 (s, 1H),  7.55                                                     (d, J=8.2Hz, 2H),  7.92 (d,                                                   J=8.2Hz, 2H). 273˜275                                                     - 209                                                                         1.37 (s, 6H), 1.44 (brs,                                                    2H),  1.88 (brs, 2H),                                                         2.50˜2.65 (m, 4H),                                                      2.78 (t, J=7.3Hz, 2H),  5.45                                                  (s, 2H),  7.10˜7.14                                                     (m, 1H),  7.22˜7.29                                                     (m, 2H),  7.43 (d, J=8.4Hz,                                                   2H),  7.88 (d, J=8.4Hz, 2H),                                                   8.05˜8.10 (m, 1H),                                                     8.35˜8.40 (m, 1H).                                                      223˜224                       - 210                                                                                                                     1.28 (s, 6H), 1.38 (s,                                                      6H),  1.52 (brs, 2H),  1.66                                                   (brs, 2H),  2.60 (brs, 4H),                                                   5.44 (s, 2H),  7.10˜7.1                                                 8 (m, 1H),  7.22 (s, 1H),                                                     7.24˜7.31 (m, 1H),                                                      7.42 (d, J=8.4Hz, 2H),  7.88                                                  (d, J=8.4Hz, 2H),  8.08                                                       (brs, 1H),  8.35˜8.41                                                   (m, 1H),  12.75 (brs, 1H).                                                    289˜290                       - 211                                                                                                                     1.32 (s, 6H), 1.43 (s,                                                      6H),  1.64˜1.75 (m,                                                     2H),  2.97 (t, J=6.4Hz, 2H),                                                   3.08 (t, J=6.4Hz, 2H),                                                       3.93 (s, 3H),  7.43 (d,                                                       J=8.4Hz, 2H),  7.80 (s, 1H),                                                   8.07 (d, J=8.4Hz, 2H).                                                       137.5˜138                  __________________________________________________________________________

Example 211 Preparation of4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)pyrazolo[5,4-a]-phenazin-3-yl]benzoicacid

Step 1

Preparation of methyl4-(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1(2H)-phenazinon-2-yl-carbonyl)benzoate##STR265##

A solution of 0.2 ml of dimethyl sulfoxide in 1 ml of methylene chloridewas dropped into a solution of 0.124 ml of oxalyl chloride in 10 ml ofmethylene chloride cooled to -60° C., followed by the stirring for 5minutes. A solution of 0.5g of methyl4-[(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1(2H)-phenazinon-2-yl)hydroxymethyl]benzoatein 10 ml of methylene chloride was dropped into the solution preparedabove. The obtained mixture was stirred for 15 minutes, followed by thedropwise addition of 0.954 ml of triethylamine: The temperature of thereaction mixture was raised to room temperature. The resulting mixturewas stirred for 30 minutes, followed by the addition of water. Theobtained mixture was extracted with methylene chloride. The organicphase was washed with water and a saturated aqueous solution of commonsalt, dried over anhydrous magnesium sulfate and concentrated in avacuum. The residue was purified by silica gel chromatography(developer: 5% ethyl acetate/hexane) to give 0.248 g of the titlecompound as a pale-yellow oil. ¹ HMN(400 MHz, CDCl₃) δ: 1.34(s, 6H),1.40(s, 6H), 1.83(s, 4H), 2.81-2.87(m, 2H), 2.98-3.04(m, 2H), 3.96(s,3H), 7.67(d, J=8.6Hz, 2H), 8.14(d, J=8.6Hz, 2H).

Step 2

Preparation of methyl4-(4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethylpyrazolo[5,4-a]phenazin-3-yl)benzoate##STR266##

0.23 g of methyl4-(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-1(2H)-phenazinon-2-yl-carbonyl)benzoatewas dissolved in 10 ml of methanol, followed by the addition of 0.04 mlof hydrazine monohydrate. The obtained mixture was heated under refluxfor one hour and cooled with ice to precipitate crystals. The crystalswere recovered by filtration, washed with a small amount of methanol anddried in a vacuum to give 0.16 g of the title compound as a white solid.

M.p.: 250 to 252° C.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.34(s, 6H), 1.36(s, 6H), 1.80(s, 4H),3.16-3.25(m, 4H), 3.95(s, 3H), 7.83(d, J=8.6Hz, 2H), 8.12(d, J=8.6Hz,2H).

Step 3

Preparation of4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)-pyrazolo[5,4-a]phenazin-3-yl]benzoicacid ##STR267##

0.20 g of methyl4-(4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethylpyrazolo[5,4-a]phenazin-3-yl)benzoatewas dissolved in 10 ml of N,N-dimethylformamide and the obtainedsolution was cooled to 0C. 0.04 g of sodium hydride was added to thesolution, followed by the stirring for 10 minutes. 0.09 g of 3-picolylchloride hydrochloride was added to the resulting mixture, followed bythe stirring for 10 minutes. The obtained mixture was further stirred atroom temperature for 30 minutes, followed by the addition of a saturatedaqueous solution of ammonium chloride. The obtained mixture wasextracted with ethyl acetate. The organic phase was washed with waterand a saturated aqueous solution of common salt, dried over anhydrousmagnesium sulfate and concentrated in a vacuum. The residue was washedwith hexane/diisopropyl ether and dried in a vacuum to give 0.15 g of alight-brown powder.

This powder was dissolved in 15 ml of ethanol, followed by the additionof 5 ml of a 5N aqueous solution of sodium hydroxide. The obtainedmixture was stirred at room temperature for 4 hours, followed by theaddition of dilute hydrochloric acid under stirring. The crystals thusprecipitated were recovered by filtration, washed with water and driedin a vacuum to give 0.1 g of the title compound as a white solid.

M.p.: 265 to 267° C.

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.13(s, 6H), 1.27(s, 6H), 1.73(s, 4H), 3.16(s, 4H), 6.02(s, 2H),7.29-7.34(m, 1H), 7.50-7.55(m, 1H), 7.83(d, J=8.1Hz, 2H), 8.01(d,J=8.1Hz, 2H), 8.42-8.46(m, 2H).

The compounds of Examples 212 and 213 were prepared in a similar mannerto that described in Example 211.

    __________________________________________________________________________       Structural                                                                   Ex. Formula .sup.1 H-NMR (400 MHz, DMSO-d.sub.6) δ m.p. (°                                                 C.)                               __________________________________________________________________________      212                                                                                                                       0.98 (s, 6H), 1.24 (s, 6H),                                                  1.67 (s, 4H), 3.18 (s, 4H),                                                  6.07 (s, 2H),  6.77 (d,                                                       =8.0Hz, 1H),  7.20˜7.25                                                 (m, 1H),  7.63˜7.69 (m,                                                 1H),  7.83 (d, J=8.0Hz, 2H),                                                  8.01 (d, J=8.0Hz, 2H),                                                        8.48˜8.53 (m, 1H).                                                      286˜282                        - 213                                                                                                                    1.28 (s, 6H), 1.32 (s, 6H),                                                  1.77 (s, 4H), 3.10 (s, 3H),                                                  4.31 (s, 3H),  7.81 (d,                                                       J=7.6Hz, 2H),  8.00 (d,                                                       J=7.6Hz, 2H). 300                 __________________________________________________________________________

Example 214 Preparation of4-[7,8,9,10-tetrahydro-7,7,10,10-tetra-methyl-1-(3-pyridylmethyl)pyrrolo[2,3-a]phenazin-3-yl]benzoicacid ##STR270##

0.07 g of ethyl4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethylpyrrolo[2,3-a]phenazin-3-yl)benzoatewas dissolved in 10 ml of 1,4-dioxane, followed by the addition of 0.03g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The obtained mixture washeated under reflux overnight and concentrated in a vacuum. The obtainedresidue was purified by silica gel chromatography (developer: 30% ethylacetate/hexane) to give 0.05 g of a light-brown powder.

This powder was dissolved in 10 ml of ethanol, followed by the additionof 5 ml of a 5N aqueous solution of sodium hydroxide. The obtainedmixture was stirred under heating at 60° C. for one hour and cooled byallowing to stand. Dilute hydrochloric acid was added to the resultingreaction mixture under stirring to precipitate crystals. The crystalswere recovered by filtration, washed with water and dried in a vacuum togive 0.03 g of the title compound as a pale-yellow solid.

M.p.: 286 to 288° C.

¹ H-NMR(400 MHz, DMSO-d₆) δ: 1.16(s, 6H), 1.36(s, 6H), 1.82(s, 4H),6.31(s, 2H), 7.22-7.28(m, 1H), 7.34-7.39(m, 1H), 7.68(d, J=8.8Hz, 1H),7.85(d, J=8.2Hz, 2H), 8.03(d, J=8.2Hz, 2H), 8.15(s, 1H), 8.27(d,J=8.8Hz.sub., 1H), 8.36-8.44(m, 2H)

Referential Example 1 Preparation of5,6,7,8-tetrahydro-2,3-diisopropyl-8-quinoxalinone

Step 1

Preparation of 5,6,7,8-tetrahydro-2,3-diisopropylquinoxaline ##STR271##

8.7 g of 2,5-dimethyl-3,4-hexanedione and 11.2 ml of1,2-cyclohexanediamine were dissolved in 20 ml of acetic acid. Theobtained solution was heated under reflux for 30 hours, cooled byallowing to stand, and poured into water, followed by the extractionwith ethyl acetate. The organic phase was washed with a saturatedaqueous solution of sodium hydrogencarbonate and a saturated aqueoussolution of common salt, dried over anhydrous magnesium sulfate, andconcentrated in a vacuum. The obtained residue was purified by silicagel chromatography (developer: 5% ethyl acetate/hexane) to give 6.8 g ofthe title compound as a colorless oil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.25(d, J=6.8Hz, 12H), 1.84-1.92(m, 4H),2.83-2.90(m, 4H), 3.23-3.34(m, 2H).

Step 2

Preparation of 5,6,7,8-tetrahydro-2,3-diisopropyl-8-quinoxalinone##STR272##

1.5 g of 5,6,7,8-tetrahydro-2,3-diisopropyl-quinoxaline was dissolved in10 ml of acetic acid, followed by the dropwise addition of a solution of1.0 g of chromic acid anhydride in acetic acid (6 ml)/water (1 ml). Theobtained mixture was stirred at 80° C. for 2 hours, cooled by allowingto stand, and poured into water, followed by the extraction with ethylacetate. The organic phase was washed with a saturated aqueous solutionof sodium hydrogencarbonate and a saturated aqueous solution of commonsalt, dried over anhydrous magnesium sulfate, and concentrated in avacuum. The obtained residue was purified by silica gel chromatography(developer: 10% ethyl acetate/hexane) to give 0.6 g of the titlecompound as a brown solid.

M.p.: 92 to 94° C.

¹ HMN(400 MHz, CDCl₃) δ: 1.28(d, J=6.8Hz, 6H), 1.32(d, J=6.8Hz, 6H),2.16-2.22(m, 4H), 2.75-2.78(m, 2H), 3.11-3.14(m, 2H), 3.33-3.43(m, 2H).

Referential Example 2 Preparation of1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethylphenazin-1-one

Step 1

Preparation of 3,3,6,6-tetramethyl-1,2-cyclohexanedione ##STR273##

44.6 g of sodium (40% oily dispersion) was suspended in 1 l of xylene ina nitrogen atmosphere. The obtained suspension was heated to 100° C. Asolution of 50 g of ethyl 2,2,5,5-tetramethylhexane-dicarboxylate in 100ml of xylene was dropped into the suspension in 30 miniutes. Theobtained mixture was stirred for 2 hours, and cooled to room temperatureby allowing to stand and then using ice. 100 ml of a 50% aqueoussolution of sulfuric acid was carefully dropped into the mixture,followed by the extraction with ethyl acetate. The organic phase waswashed with water and a saturated aqueous solution of common salt, driedover magnesium sulfate, and concentrated in a vacuum. The obtainedresidue was purified by silica gel chromatography (developer: 5% ethylacetate/hexane) to give 28 g of a pale-yellow oil.

This oil was dissolved in 70 ml of acetic acid, followed by the dropwiseaddition of a solution of 18 g of chromic acid anhydride in acetic acid(70 ml)/water (9 ml) at 10° C. The obtained mixture was brought to roomtemperature, stirred for 3 hours, and poured into 2 l of water toprecipitate crystals. The crystals were recovered by filtration, washedwith water and dried in a vacuum to give 19.5 g of the title compound asa yellow solid.

M.p.: 109 to 111° C.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.16(s, 12H) , 1.87(s, 4H)

Step 2

Preparation of 1,2,3,4,6,7,8,9-octahydro-1,1,4,4-tetramethylphenazine##STR274##

20.0 g of 3,3,6,6,-tetramethyl-1,2-cyclohexanedione and 20 ml of1,2-cyclohexanediamine were dissolved in 20 ml of acetic acid. Theobtained solution was heated under reflux for 6 hours, cooled byallowing to stand, and poured into water, followed by the extractionwith ethyl acetate. The organic phase was washed with a saturatedaqueous solution of sodium hydrogencarbonate and a saturated aqueoussolution of common salt, dried over anhydrous magnesium sulfate, andconcentrated in a vacuum. The obtained residue was purified by silicagel chromatography (developer: 5% ethyl acetate/hexane) to give 16.0 gof the title compound as a colorless oil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.28(s, 12H), 1.75(s, 4H), 1.86-1.90(m, 4H),2.83-2.88(m, 4H).

Step 3

Preparation of1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethylphenazin-1-one ##STR275##

8.0 g of 1,2,3,4,6,7,8,9-octahydro-1,1,4,4-tetramethylphenazine wasdissolved in 30 ml of acetic acid, followed by the dropwise addition ofa solution of 4.9 g of chromic acid anhydride in acetic acid (30ml)/water (4 ml). The obtained mixture was stirred at 80° C. for 30minutes, cooled by allowing to stand, and poured into water, followed bythe extraction with ethyl acetate. The organic phase was washed with asaturated aqueous solution of sodium hydrogencarbonate and a saturatedaqueous solution of common salt, dried over anhydrous magnesium sulfateand concentrated in a vacuum. The obtained residue was purified bysilica gel chromatography (developer: 20% ethyl acetate/hexane) to give1.6 g of the title compound as a brown oil.

¹ H-NMR(400 MHz, CDCl₃) δ: 1.33(s, 6H), 1.35(s, 6H), 1.81(s, 4H),2.15-2.23(m, 2H), 2.77(dd, J=5.9, 6.9Hz, 2H), 3.12(dd, J=5.9, 5.9Hz, 2H)

Referential Example 3 Preparation of6,7,8,9-tetrahydro-6,6,9,9-tetramethyl-thianaphtho[2,3-b]-cyclohexan-1-one##STR276## Step 1 Preparation of 2,5-dimethyl-5-(2-thienyl)-2-hexanol##STR277##

70 ml of a 3 mol/l solution of methylmagnesium bromide in diethyl etherwas dropped into 200 ml of a solution of 20.4 g of ethyl4-methyl-4-(2-thienyl)valerate in anhydrous diethyl ether under coolingwith ice, followed by the stirring for 10 minutes. The obtained mixturewas further stirred at room temperature for 2.5 hours. The resultingmixture was cooled with ice, and a saturated aqueous solution ofammonium chloride was carefully added to the mixture to decompose excessreagent. The organic phase was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous magnesium sulfate and distilledin a vacuum to remove the solvent, thus giving 19.8 g of the titlealcohol as a colorless oil.

¹ H-NMR(400 MHz, CDCl₃) δ (ppm) 1.16(s, 6H), 1.30-1.38(m, 2H), 1.38(s,6H), 1.65-1.72(m, 2H), 6.77-6.80(m, 1H), 6.88-6.92(m, 1H), 7.13(d,J=5.0Hz, 1H).

Step 2

Preparation of 4,5,6,7-tetrahydro-4,4,7,7-tetramethylthianaphthene##STR278##

19.8 g of 2,5-dimethyl-5-(2-thienyl)-2-hexanol was added to 150 ml of adichloromethane suspension of 16 g of aluminum chloride under coolingwith ice. The obtained mixture was stirred for 30 minutes and pouredonto ice-water, followed by the extraction with ethyl acetate. Theorganic phase was washed with water, a saturated aqueous solution ofsodium hydrogencarbonate and a saturated aqueous solution of common saltsuccessively, dried over anhydrous magnesium sulfate, and concentratedin a vacuum. The obtained residue was purified by silica gelchromatography (developer: n-hexane) to give 9.3 g of a colorless oil.

¹ H-NMR(400 MHz, CDCl₃) δ (ppm): 1.23(s, 6H), 1.33(s, 6H), 1.65-1.75(m,4H), 6.83(d, J=5.4Hz, 1H), 7.15(d, J=5.4Hz, 1H).

Step 3

Preparation of6,7,8,9-tetrahydro-6,6,9,9-tetra-methylthianaphtho[2,3-b]-cyclohexan-1-one##STR279##

9.3 g of 4,5,6,7-tetrahydro-4,4,7,7-tetramethylthianaphthene and 9.4 gof chloride of monoethyl succinate were added to 100 ml of methylenechloride, followed by the dropwise addition of 6.7 ml of a 1M solutionof stannic chloride in methylene chloride under cooling with ice. Theobtained mixture was stirred at room temperature for 2.5 hours andpoured onto ice-water, followed by the extraction with 200 ml of ethylacetate. The organic phase was washed with water, a saturated aqueoussolution of sodium hydrogencarbonate and a saturated aqueous solution ofcommon salt successively, dried over anhydrous magnesium sulfate, andconcentrated in a vacuum. The obtained residue was dissolved in 100 mlof ethanol, followed by the addition of 50 ml of a 5N aqueous solutionof sodium hydroxide. The obtained mixture was stirred at roomtemperature for 2 hours and acidified with dilute hydrochloric acid,followed by the addition of ethyl acetate. The organic phase was washedwith a saturated aqueous solution of common salt, dried over anhydrousmagnesium sulfate, and distilled in a vacuum to remove the solvent. Theobtained solid residue was washed with n-hexane to give 12.6 g of awhite solid.

This solid was suspended in 150 ml of diethylene glycol, followed by theaddition of 8.6 g of sodium hydroxide and 6.4 g of hydrazinemonchydrate. The obtained mixture was vigorously stirred at 180° C. in anitrogen stream for 4 hours, cooled by allowing to stand, and pouredinto cooled dilute hydrochloric acid, followed by the extraction with200 ml of ethyl acetate. The organic phase was washed with a saturatedaqueous solution of common salt, dried over anhydrous magnesium sulfate,and concentrated in a vacuum to give 10.4 g of a yellow oil.

100 g of polyphosphoric acid was added to this oil. The obtained mixturewas stirred at 170° C. in a nitrogen stream for 2 hours, cooled byallowing to stand, and poured onto ice-water, followed by the extractionwith 200 ml of ethyl acetate. The organic phase was washed with water, asaturated aqueous solution of sodium hydrogencarbonate and a saturatedaqueous solution of common salt successively, dried over anhydrousmagnesium sulfate, and concentrated in a vacuum. The obtained residuewas purified by silica gel chromatography (developer: 2% ethylacetate/n-hexane) to give 7.0 g of the title compound as a yellow oil.

¹ H-NMR(400 MHz, CDCl₃) δ (ppm): 1.28(s, 6H), 1.36(s, 6H), 1.66(s, 4H),2.08-2.16(m, 2H), 2.53(t, J=6.8Hz, 2H), 2.96(t, J=6.8Hz, 2H).

What is claimed is:
 1. A compound of the formula ##STR280## wherein n is3, R¹ is H or carboxy-protecting group, and R² and ³ are independentlyH, halogeno or a linear lower alkyl.
 2. A pharmaceutical compositioncomprising a compound of claim 1 together with a pharmaceuticallyacceptable diluent.
 3. A method of treating or preventingimmunosuppression in organ transplantation, autoimmune disease and/ormalignant neoplasm, comprising administering to a person in need of samean effective amount of a mono- or polyenic carboxylic acid derivative orphysiologically acceptable salts thereof according to claim
 1. 4. Themethod according to claim 3, wherein the autoimmune disease ispsoriasis, rheumatoid arthritis, multiple sclerosis, thrombocytopenia,insulin-dependent diabetes mellitus, atopic dermatitis or systemic lupuserythematosus.
 5. The method according to claim 3, wherein the malignantneoplasm is acute promyelocytic leukemia or acute myelocytic leukemia.